Lipoprotein(a): from Causality to Treatment

Abstract

Purpose of review: This paper reviews the evidence why lipoprotein(a) (Lp(a)) is a causal risk factor for cardiovascular disease and how high Lp(a) concentrations should be managed now and with an outlook to the future.

Review findings: No optimal and widely available animal models exist to study the causality of the association between Lp(a) and cardiovascular disease. This has been a major handicap for the entire field. However, genetic studies turned the page. Already in the early 1990s, the principle of Mendelian randomization studies was applied for the first time ever (even if they were not named so at that time). Genetic variants of the LPA gene such as the apolipoprotein(a) isoform size, the number and sum of kringle IV repeats and later single nucleotide polymorphisms are strongly associated with life-long exposure to high Lp(a) concentrations as well as cardiovascular outcomes. This evidence provided a basis for the development of specific Lp(a)-lowering drugs that are currently in clinical testing phase. Lp(a) is one of the most important genetically determined risk factors for cardiovascular disease. With the specific Lp(a)-lowering therapies, we might get tools to fight this common risk factor in case the outcome trials will be positive.

Keywords: Cardiovascular disease; Epidemiology; Genetics; Lipoprotein(a); mRNA targeting therapy.

Fig. 1

This figure is based on calculations for the Lp(a) Consensus statement of the European Atherosclerosis Society (presented as Fig. 6 therein [••]) and presents the main message in a simplified form. The y-axis shows the estimated absolute lifetime risk for major atherosclerotic cardiovascular events (ASCVD) among 415,274 participants of European ancestry in the UK Biobank. Participants are divided into categories of baseline estimated lifetime risk of 5% which equals no or a low number of traditional risk factors, 15% (medium number of risk factors), and 25% (high number of risk factors), respectively, calculated using the Joint British Societies (JBS3) Lifetime Risk Estimating algorithm (based on traditional risk factors age, sex, blood cholesterol, blood pressure, smoking, diabetes, family history of heart attacks in early life, and BMI). For each of these three baseline risk categories, the additional risk attributable to increasing Lp(a) concentrations of 50 mg/dL (yellow bars) or 150 mg/dL (red bars) measured at baseline compared to those with the median Lp(a) concentration of 7 mg/dL (green bars) is calculated and added to the baseline risk to provide the global absolute risk. This incremental increase in risk caused by higher Lp(a) concentrations of 50 mg/dL and 150 mg/dL was estimated by adding Lp(a) as an independent exposure to the JBS3 risk estimating algorithm. For example, for a person with a baseline risk of 25% and an Lp(a) concentration of 50 mg/dL, the absolute risk of a major cardiovascular event increases by 10% from 25 to 35% (versus a person with an Lp(a) of 7 mg/dL). In case of an Lp(a) concentration if 150 mg/dL the risk increases by 43% from 25 to 68%. The reduction of modifiable traditional risk factors is therefore the ultimate goal in case of elevated Lp(a) concentrations to decrease the global risk of a given person

Fig. 2

Schematic illustration of a Mendelian randomization approach using the example of lipoprotein(a) [Lp(a)]. Observational studies showed a significant association of high Lp(a) concentrations with cardiovascular disease. Genetic variants which show a strong association with high Lp(a) concentrations are used as genetic instrument (e.g., small apo(a) isoforms, low number of K-IV repeats, certain SNPs associated with high Lp(a) concentrations). When these instruments show also an association with cardiovascular disease, a causal association between Lp(a) concentrations and cardiovascular disease is strongly supported and a reverse causation might be excluded. Pleiotropy has to be excluded in the sense that the genetic variant affects the outcome only via the biomarker and not via other independent pathways. (Reproduced from [10], https://www.sciencedirect.com/science/article/pii/S1043661823001998?via%3Dihub; Creative Commons user license; https://creativecommons.org/licenses/by/4.0/)