Lipoprotein(a): Knowns, unknowns and uncertainties.

Over the last 10 years, there have been advances on several aspects of lipoprotein(a) which are reviewed in the present article. Since the standard immunoassays for measuring lipoprotein(a) are not fully apo(a) isoform-insensitive, the application of an LC-MS/MS method for assaying molar concentrations of lipoprotein(a) has been advocated. Genome wide association, epidemiological, and clinical studies have established high lipoprotein(a) as a causal risk factor for atherosclerotic cardiovascular diseases (ASCVD). However, the relative importance of molar concentration, apo(a) isoform size or variants within the LPA gene is still controversial. Lipoprotein(a)-raising single nucleotide polymorphisms has not been shown to add on value in predicting ASCVD beyond lipoprotein(a) concentrations. Although hyperlipoproteinemia(a) represents an important confounder in the diagnosis of familial hypercholesterolemia (FH), it enhances the risk of ASCVD in these patients. Thus, identification of new cases of hyperlipoproteinemia(a) during cascade testing can increase the identification of high-risk individuals. However, it remains unclear whether FH itself increases lipoprotein(a). The ASCVD risk associated with lipoprotein(a) seems to follow a linear gradient across the distribution, regardless of racial subgroups and other risk factors. The inverse association with the risk of developing type 2 diabetes needs consideration as effective lipoprotein(a) lowering therapies are progressing towards the market. Considering that Mendelian randomization analyses have identified the degree of lipoprotein(a)-lowering that is required to achieve ASCVD benefit, the findings of the ongoing outcome trial with pelacarsen will clarify whether dramatically lowering lipoprotein(a) levels can reduce the risk of ASCVD.