Oral strategies to target proprotein convertase subtilisin/kexin type 9 and lipoprotein(a): the new frontier of lipid lowering

Hypercholesterolaemia is a major causal risk factor for ischaemic heart disease and related deaths, 1 and low-density lipoprotein cholesterol (LDL-C) is the primary target in dyslipidaemia guidelines.While epidemiological and clinical data have clearly demonstrated the benefits of widely lowering LDL-C levels in patients at very high and high cardiovascular risk, real-world data show that only a limited number of patients achieve the desired levels, which have become more stringent in recent guidelines. 2 It is also important to emphasize that lowering LDL-C to very low levels does not eliminate cardiovascular risk.In fact, all apolipoprotein B (apoB)-containing lipoproteins small enough to penetrate the arterial wall are atherogenic and include not only LDL but also remnants and lipoprotein(a) (Lp(a)), all of which contribute to atherogenesis and residual lipid-related cardiovascular risk beyond LDL-C levels.As a result, the new strategies for the treatment of hyperlipidaemia aim to implement the use of LDL-C-lowering therapies to increase patient adherence but also to address the residual risk associated with other apoB-containing lipoproteins. 3Advances in medicine have made it possible to develop new biological and chemical therapies to target specific pathways in lipid metabolism.In this context, new compounds in clinical development in 2023 will explore the possibility of targeting proprotein convertase subtilisin/kexin type 9 (PCSK9) or blocking Lp(a) formation through oral administration (Figure 1).