Abstract
Lipoprotein(a) [Lp(a)] is a complex circulating lipoprotein, and it has been almost six decades since its discovery and naming by Kare Berg, a Norwegian geneticist. 1 Evidence is aplenty from epidemiological and genetic studies with regard to Lp(a) being a risk factor that is associated with coronary and noncoronary diseases such as coronary artery disease (CAD), especially in the young, ischemic stroke, carotid and intracranial stenosis, recurrent stroke in neonates, children and young adults, calcified aortic valve disease, heart failure, peripheral arterial disease, abdominal aortic aneurysm, aortic thrombosis, aortic dissection, left atrial thrombus, and retinal vascular occlusion. 2
The mechanisms involved are diverse. Besides the atherogenic properties of low-density lipoprotein (LDL)-like particles in Lp(a), which are more atherogenic and have a longer half-life than normal LDL, this molecule mediates signaling processes driving angiogenesis. It is also involved in cellular inflammation and proliferation, cytokine formation, and antifibrinolytic activity, making a prothrombotic milieu. 2
Management and interpretation of Lp(a) levels pose a challenging situation because of isoform sensitivity assay and the unmet need for an ethnic threshold that need to be defined. 2
The genetic variables predisposed to high Lp(a) levels probably explain the lack of significant favorable effects of therapeutic lifestyle modifications on serum Lp(a) concentrations. 2 Conventional lipid-lowering drugs such as statins, ezetimibe, bempedoic acid, fibrates, and omega-3 fatty acids have shown inconsistent results with regard to lowering of Lp(a) concentration. 2 Cascade screening and aggressive prevention and control of all modifiable risk factors should be considered first. 2 The sole treatment that the Food and Drug Administration (FDA) has approved is lipoprotein apheresis in patients with confirmed cardiovascular disease (CVD) progression and elevated Lp(a) levels greater than 60 mg/dL.3, 4
Several newer research molecules are emerging that aim at lowering Lp(a), and many are in phase 1 or phase 2 trials. Antisense oligonucleotides (ASOs) such as pelacarsen, small interfering RNAs (siRNA) such as olpasiran, lepodisiran, LY3819469, zerlasiran, and an oral molecule muvalaplin have all shown to reduce Lp(a) concentration varying from 80% to 94%. 5 The therapeutic impact of these newer drugs will emerge only after completion of ongoing trials and research.
Godfey Tabowei in his praise-worthy article titled “Unveiling Lipoprotiein (a): A New Frontier in Heart Health” (published in this issue) has reviewed all the intricate details of Lp(a) as a mystery molecule including its role in atherogenic and nonatherogenic disease entities and the possible therapeutic options that the future is going to offer to lower Lp(a), which may help to favorably modify CVD in the near future.