Role of lipoprotein(a) in atherosclerotic cardiovascular disease: A review of current and emerging therapies

Abstract

Lipoprotein(a), or Lp(a), is structurally like low‐density lipoprotein (LDL) but differs in that it contains glycoprotein apolipoprotein(a) [apo(a)]. Due to its prothrombotic and proinflammatory properties, Lp(a) is an independent risk factor for atherosclerotic cardiovascular disease (ASCVD) and aortic valve stenosis. Lp(a) levels are genetically determined, and it is estimated that 20%–25% of the global population has an Lp(a) level ≥50 mg/dL (or ≥125 nmol/L). Diet and lifestyle interventions have little to no effect on Lp(a) levels. Lipoprotein apheresis is the only approved treatment for elevated Lp(a) but is time‐intensive for the patient and only modestly effective. Pharmacological approaches to reduce Lp(a) levels and its associated risks are of significant interest; however, currently available lipid‐lowering therapies have limited effectiveness in reducing Lp(a) levels. Although statins are first‐line agents to reduce LDL cholesterol levels, they modestly increase Lp(a) levels and have not been shown to change Lp(a)‐mediated ASCVD risk. Alirocumab, evolocumab, and inclisiran reduce Lp(a) levels by 20‐25%, yet the clinical implications of this reduction for Lp(a)‐mediated ASCVD risk are uncertain. Niacin also lowers Lp(a) levels; however, its effectiveness in mitigating Lp(a)‐mediated ASCVD risk remains unclear, and its side effects have limited its utilization. Recommendations for when to screen and how to manage individuals with elevated Lp(a) vary widely between national and international guidelines and scientific statements. Three investigational compounds targeting Lp(a), including small interfering RNA (siRNA) agents (olpasiran, SLN360) and an antisense oligonucleotide (pelacarsen), are in various stages of development. These compounds block the translation of messenger RNA (mRNA) into apo(a), a key structural component of Lp(a), thereby substantially reducing Lp(a) synthesis in the liver. The purpose of this review is to describe current recommendations for screening and managing elevated Lp(a), describe the effects of currently available lipid‐lowering therapies on Lp(a) levels, and provide insight into emerging therapies targeting Lp(a).

Estimating the Prevalence and Characteristics of Patients Potentially Eligible for Lipoprotein(a)-Lowering Therapies in a Real-World Setting

“…Some nutraceuticals (including L-carnitine, curcumin and coenzyme Q10) mildly (≈−10%) improve this parameter, even though their effect is substantially irrelevant from both a clinical and prognostic point of view [35,36]. Statins do not lower Lp(a): they partly balance its negative effect on the ASCVD risk for concentrations < 50 mg/dL, but not for higher values [8,37]. Prolonged-release (PR) nicotinic acid is the only agent able to reduce Lp(a) by 20-30%, but it is not always well tolerated [38].…”

“…The prothrombotic effect of Lp(a) can be partially counteracted via the use of antiplatelet drugs, but the evidence is greater in patients with ASCVD [7]. Emerging lipid-lowering drugsnamely small interfering ribonucleic acid (siRNA) agents olpasiran (LY3819469, SLN360, formerly known as AMG-890, ARO-LPA) and the second-generation antisense oligopeptide pelacarsen (also known as AKCEA-APO[a]-LRx)-are being developed to specifically interfere with Lp(a) synthesis by preventing the protein translation of apo(a) messenger RNA (mRNA) into apo(a) [8]. The ultimate objective of this therapy is to genetically silence LPA, reduce apo(a) production and lower the circulating Lp(a) levels, of consequence [9].…”

Successful Treatment of Severe Case of Lipid Overload Syndrome with Pancreatitis and Pneumonia: A Case Report

“…For example, fenofibrate can activate peroxisome proliferator-activated receptor alpha (PPAR-α), thereby increasing the activity of tissue lipoprotein lipase and the breakdown of triglycerides in very low-density lipoprotein (VLDL), thus regulating abnormal lipid levels 16 Niacin can also lower levels of lipoprotein(a) [Lp(a)], thereby regulating lipid abnormalities. 17 It’s worth noting that consuming 2–4 grams of Omega-3 fatty acids per day can also lower triglyceride levels. 18 Additionally, when statin therapy is intensified, inflammation and hyperlipidemia can be controlled, potentially altering their relative contribution to future cardiovascular event risks.…”

Triangel oder Mahler-Hammer im Konzert von kardiovaskulären Risikofaktoren

“…vielmehr die Bildung von Apo(a) selbst therapeutisch reduziert bzw. verhindert werden sollte, um kardiovaskuläre Ereignisse zu verhindern [19]. Hierbei macht man sich die Antisense-Therapie zunutze, bei der die mRNA als Bauanleitung für Apo(a) spezifisch in der Leber durch den entsprechenden Gegenstrang (Antisense-Strang) abgebaut wird -sie ist aktuell die effektivste medikamentöse Maßnahme in der Lp(a)-Absenkung [20], während die Lipoproteinapherese die bisher einzige zugelassene Methode in der Behandlung von kardiovaskulären Ereignissen durch erhöhtes Lp(a) in Deutschland ist [21].…”

“…Hierzu befinden sich mittlerweile 2 Medikamente (Pelacarsen, Olpasiran) in der Studienphase III (Lp(a)-Horizon, OCEAN). Mit ersten Outcome-Ergebnissen ist 2025 zu rechnen [19].…”