Effects of mipomersen, an apolipoprotein B100 antisense, on lipoprotein (a) metabolism in healthy subjects

Nandakumar, Renu; Matveyenko, Anastasiya; Thomas, Tiffany; Pavlyha, Marianna; Ngai, Colleen; Holleran, Steve; Ramakrishnan, Rajasekhar; Ginsberg, Henry N.; Karmally, Wahida; Marcovina, Santica M.; Reyes‐Soffer, Gissette

doi:10.1194/jlr.p082834

Cited by 46 publications

(29 citation statements)

References 36 publications

(55 reference statements)

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“…Interventional studies on plasma Lp(a) levels with different lipid-lowering drugs exhibiting various mechanisms of action (PCSK9 inhibitor, 18 apoB100 antisense oligonucleotide, 45 CETP inhibitor, 46,47 ezetimibe, 48 fibrates, 48,49 and statins 37,[49][50][51] ) also suggested that plasma Lp(a) reduction is associated with a decrease in the total or VLDL apoE concentration. A decrease in the Lp(a) production rate is the most frequently offered explanation for Lp(a) reduction, irrespective of treatment.…”

Section: Discussionmentioning

confidence: 99%

VLDL (Very-Low-Density Lipoprotein)-Apo E (Apolipoprotein E) May Influence Lp(a) (Lipoprotein [a]) Synthesis or Assembly

Croyal¹,

Blanchard

Ouguerram³

et al. 2020

ATVB

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To clarify the association between PCSK9 (proprotein convertase subtilisin/kexin type 9) and Lp(a) (Lipoprotein [a]), we studied Lp(a) kinetics in patients with loss-of-function and gain-of-function PCSK9 mutations and in patients in whom extended-release niacin reduced Lp(a) and PCSK9 concentrations.APPROACH AND RESULTS: Six healthy controls, 9 heterozygous patients with familial hypercholesterolemia (5 with low-density lipoprotein receptor [LDLR] mutations and 4 with PCSK9 gain-of-function mutations) and 3 patients with heterozygous dominant-negative PCSK9 loss-of-function mutations were included in the preliminary study. Eight patients were enrolled in a second study assessing the effects of 2 g/day extended-release niacin. Apolipoprotein kinetics in VLDL (very-lowdensity lipoprotein), LDL (low-density lipoprotein), and Lp(a) were studied using stable isotope techniques. Plasma Lp(a) concentrations were increased in PCSK9-gain-of-function and familial hypercholesterolemia-LDLR groups compared with controls and PCSK9-loss-of-function groups (14±12 versus 5±4 mg/dL; P=0.04), but no change was observed in Lp(a) fractional catabolic rate. Subjects with PCSK9-loss-of-function mutations displayed reduced apoE (apolipoprotein E) concentrations associated with a VLDL-apoE absolute production rate reduction. Lp(a) and VLDL-apoE absolute production rates were correlated (r=0.50; P<0.05). ApoE-to-apolipoprotein (a) molar ratios in Lp(a) increased with plasma Lp(a) (r=0.96; P<0.001) but not with PCSK9 levels. Extended-release niacin-induced reductions in Lp(a) and VLDL-apoE absolute production rate were correlated (r=0.83; P=0.015). In contrast, PCSK9 reduction (−35%; P=0.008) was only correlated with that of VLDL-apoE absolute production rate (r=0.79; P=0.028).CONCLUSIONS: VLDL-apoE production could determine Lp(a) production and/or assembly. As PCSK9 inhibitors reduce plasma apoE and Lp(a) concentrations, apoE could be the link between PCSK9 and Lp(a).

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Section: Discussionmentioning

confidence: 99%

VLDL (Very-Low-Density Lipoprotein)-Apo E (Apolipoprotein E) May Influence Lp(a) (Lipoprotein [a]) Synthesis or Assembly

Croyal¹,

Blanchard

Ouguerram³

et al. 2020

ATVB

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“…In statin-treated patients, the fractional turnovers of apo(a) and apoB proteins within Lp(a) are similar, thus reflecting a tight coupling of these protein components. A recent kinetic study relative to the production rate of Lp(a) suggested that the hepatic availability of apoB is unlikely to be rate-limiting for the assembly and production of Lp(a) particles [ 54 ]. Overall, the molecular mechanisms responsible for Lp(a) catabolism still remain elusive, with several receptor systems being proposed as implicated in this process (lipoprotein receptors, toll-like and scavenger receptors, lectins, and plasminogen receptors) [ 55 ].…”

Section: Statinsmentioning

confidence: 99%

Lipoprotein(a) Lowering—From Lipoprotein Apheresis to Antisense Oligonucleotide Approach

Greco

Sirtori

Corsini

et al. 2020

JCM

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It is well-known that elevated lipoprotein(a)—Lp(a)—levels are associated with a higher risk of cardiovascular (CV) mortality and all-cause mortality, although a standard pharmacotherapeutic approach is still undefined for patients with high CV risk dependent on hyperlipoproteinemia(a). Combined with high Lp(a) levels, familial hypercholesterolemia (FH) leads to a greater CVD risk. In suspected FH patients, the proportion of cases explained by a rise of Lp(a) levels ranges between 5% and 20%. In the absence of a specific pharmacological approach able to lower Lp(a) to the extent required to achieve CV benefits, the most effective strategy today is lipoprotein apheresis (LA). Although limited, a clear effect on Lp(a) is exerted by PCSK9 antagonists, with apparently different mechanisms when given with statins (raised catabolism) or as monotherapy (reduced production). In the era of RNA-based therapies, a new dawn is represented by the use of antisense oligonucleotides APO(a)Lrx, able to reduce Lp(a) from 35% to over 80%, with generally modest injection site reactions. The improved knowledge of Lp(a) atherogenicity and possible prevention will be of benefit for patients with residual CV risk remaining after the most effective available lipid-lowering agents.

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“…The mechanism underlying this effect was recently the subject of a comprehensive investigation. Another option could be mipomersen, an apoB inhibitor, which could correlate with the reduction of Lp(a) ∼30% 57) ; however, it almost always causes fatty liver since it blocks the secretion of apoB-containing lipoproteins from the liver. Another emerging option could be antisense oligonucleotide (ASO) targeted to apolipoprotein(a).…”

Section: Lp(a)-lowering Therapiesmentioning

confidence: 99%

Lipoprotein(a) as an Old and New Causal Risk Factor of Atherosclerotic Cardiovascular Disease

Tada

Takamura

Kawashiri

2019

JAT

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The official journal of the Japan Atherosclerosis Society and the Asian Pacific Society of Atherosclerosis and Vascular Diseases Review Lipoprotein(a) [Lp(a)], discovered in 1963, has been associated with atherosclerotic cardiovascular disease (ASCVD) independent of other traditional risk factors, including LDL cholesterol. Lp(a) is an apolipoprotein B (apoB)-containing lipoprotein, which contains an LDL-like particle. Unlike LDL, which is a primary therapeutic target to decrease ASCVD, current guidelines recommend measuring Lp(a) for risk assessments because there is no clear evidence demonstrating the clinical benefit of decreasing Lp(a) using classical drugs such as niacin. However, recent Mendelian randomization studies indicate that Lp(a) causally correlates with ASCVD. In addition, novel drugs, including PCSK9 inhibitors, as well as antisense oligonucleotide for apo(a), have exhibited efficacy in decreasing Lp(a) substantially, invigorating a discussion whether Lp(a) could be a novel therapeutic target for further ASCVD risk reduction. This review aims to provide current understanding, and future perspectives, of Lp(a), which is currently considered a mere biomarker but may emerge as a novel therapeutic target in future clinical settings. This review aims to provide a current understanding, and future perspectives, of Lp(a), which is currently considered a mere biomarker but may emerge as a novel therapeutic target in future clinical settings. What is Lp(a)? Lp(a) is a particle containing two different elements (Fig. 1). The first element is an LDL-like particle containing an apoB-100 particle, which is insoluble in water. Reportedly, the LDL-like particle in Lp(a) is larger in size and higher in lipid content, with a density marginally lower than the LDL particle isolated from the same individual 11). The second element is a hydrophilic glycoprotein called apo(a) that shares homology with plasminogen, giving the particle atherogenic properties. Plasminogen has five kringles (KI-KV); apo(a) does not contain KI-KIII but has 10 subtypes of KIV (with KIV1, and KIV3-KIV10 have one copy, and KIV2 has one to 40 copies), and one copy of KV. The apo(a) isoform size and the Lp(a)

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Effects of mipomersen, an apolipoprotein B100 antisense, on lipoprotein (a) metabolism in healthy subjects

Cited by 46 publications

References 36 publications

VLDL (Very-Low-Density Lipoprotein)-Apo E (Apolipoprotein E) May Influence Lp(a) (Lipoprotein [a]) Synthesis or Assembly

VLDL (Very-Low-Density Lipoprotein)-Apo E (Apolipoprotein E) May Influence Lp(a) (Lipoprotein [a]) Synthesis or Assembly

Lipoprotein(a) Lowering—From Lipoprotein Apheresis to Antisense Oligonucleotide Approach

Lipoprotein(a) as an Old and New Causal Risk Factor of Atherosclerotic Cardiovascular Disease

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