LP(a): The new marker of high cardiovascular risk

Abstract

The biological functions and role in human diseases of lipoprotein (a) discovered more than 60 years ago are still not fully understood. The high homology of apo(a) with plasminogen initially leads us to think of Lp(a) as a player in the coagulation system as pro-thrombotic factor. Over the years, a solid body of evidence from biology, epidemiology and from genetics and mendelian randomization has contributed to identify Lp(a) as a causal factor of atherosclerotic coronary heart disease, aortic calcific valve stenosis and ischaemic stroke. The active involvement of Lp(a) in atherogenesis and aortic calcific valve stenosis has been demonstrated by experimental data regarding the role of oxidized phospholipids, which are the cargo of Lp(a) and the presence of a Lp(a) receptor in valve interstitial cells. In secondary prevention, patients optimally treated for low density lipoprotein cholesterol (LDL-C) but with high Lp(a) levels show a residual cardiovascular risk. To date the LDL-C affecting drugs have a marginal effect on Lp(a). Statins produce a modest increase, monoclonal PCSK9i and Inclisiran a modest decrease not sufficient to reduce significantly the risk associated to Lp(a). Only lipoprotein apheresis and obicetrapib, a CETP novel inhibitor, reduce respectively by 75% and 40% Lp(a) levels. To obtain a lifetime risk reduction of 50% similar to that achieved by reducing LDL-C of about 40 mg/dl, Lp(a) should be reduced of about 100 mg/dl. The ongoing trials on drugs such as ASO, SiRnas, assembly inhibitors and maybe in the future the gene editing could obtain these results.