Modern Approaches to Lower Lipoprotein(a) Concentrations and Consequences for Cardiovascular Diseases

Abstract

Lipoprotein(a) (Lp(a)) is a low density lipoprotein particle that is associated with poor cardiovascular prognosis due to pro-atherogenic, pro-thrombotic, pro-inflammatory and pro-oxidative properties. Traditional lipid-lowering therapy does not provide a sufficient Lp(a) reduction. For PCSK9 inhibitors a small reduction of Lp(a) levels could be shown, which was associated with a reduction in cardiovascular events, independently of the effect on LDL cholesterol. Another option is inclisiran, for which no outcome data are available yet. Lipoprotein apheresis acutely and in the long run decreases Lp(a) levels and effectively improves cardiovascular prognosis in high-risk patients who cannot be satisfactorily treated with drugs. New drugs inhibiting the synthesis of apolipoprotein(a) (an antisense oligonucleotide (Pelacarsen) and two siRNA drugs) are studied. Unlike LDL-cholesterol, for Lp(a) no target value has been defined up to now. This overview presents data of modern capabilities of cardiovascular risk reduction by lowering Lp(a) level.

Lipoprotein (a) in familial hypercholesterolaemia

“…Two, while strongly confirming the evidence for the association, at the same time predict that, to decrease ASCVD risk appreciably, Lp(a) will need to be substantially decreased in terms of its absolute concentration by novel specific pharmacological interventions, something only possible when its pretreatment levels are particularly high [5,42 ▪▪ ]. Thus, agents, which specifically reduce Lp(a) currently at various stages of development, such as olpasiran, pelacarsen and SLN360 [43 ▪▪ –45 ▪▪ ,46,47], are likely to prove most effective when Lp(a) is substantially raised. A high proportion of people with familial hypercholesterolaemia with strikingly high Lp(a) levels may thus be ideal to beneficiaries.…”

Ten things to know about ten cardiovascular disease risk factors – 2022

“…However, Lp(a) levels can be reduced with lipoprotein apheresis and other pharmacotherapies in development (e.g., antisense oligonucleotides and small interfering ribonucleic acids). [154] The ongoing Lp(a) HORIZON cardiovascular outcome study is evaluating pelacarsen (i.e., antisense oligonucleotide targeting the LPA gene messenger RNA) regarding its effects upon major adverse cardiac events. [ 154 , 155 , 156 ] Until therapies that lower Lp(a) are proven to provide health benefits, a single accurate measure of Lp(a) may be sufficient to inform on CVD risk.…”

“… [154] The ongoing Lp(a) HORIZON cardiovascular outcome study is evaluating pelacarsen (i.e., antisense oligonucleotide targeting the LPA gene messenger RNA) regarding its effects upon major adverse cardiac events. [ 154 , 155 , 156 ] Until therapies that lower Lp(a) are proven to provide health benefits, a single accurate measure of Lp(a) may be sufficient to inform on CVD risk. [157] Statins are the most recommended drug treatment for hypercholesterolemia due to their cholesterol-lowering efficacy, safety, and ASCVD benefits supported by numerous cardiovascular outcomes trials.…”

“… [154] The ongoing Lp(a) HORIZON cardiovascular outcome study is evaluating pelacarsen (i.e., antisense oligonucleotide targeting the LPA gene messenger RNA) regarding its effects upon major adverse cardiac events. [ 154 , 155 , 156 ] Until therapies that lower Lp(a) are proven to provide health benefits, a single accurate measure of Lp(a) may be sufficient to inform on CVD risk. [157] …”

Lipids and Lipoproteins in Health and Disease

“…Current approaches for reducing lipoprotein(a) levels (one of the cardiovascular risk factors) are discussed in the review, including recent studies on drugs inhibiting the synthesis of lipoprotein(a), based on antisense oligonucleotide and siRNA [ 18 ].…”