Integrating lipoprotein(a) into preventive cardiology: probably important to get the measurement right

This editorial refers to ‘Lipoprotein(a) and cardiovascular disease: sifting the evidence to guide future research’, by P.R. Kamstrup et al., https://doi.org/10.1093/eurjpc/zwae032.

The last decade has witnessed an extraordinary degree of activity highlighting the causal role of lipoprotein(a) [Lp(a)] in a range of forms of cardiovascular disease. This reflects a series of preclinical, cohort, and genomic studies that have provided important insights into both the metabolism and functional properties of Lp(a).¹ These findings have implications for the assessment of cardiovascular risk and have stimulated immense activity in drug development, including the development of small molecule inhibitors,² RNA interference biologics,^3–5 and gene editing therapeutics,⁶ with the potential to substantially lower Lp(a) levels. Accordingly, these agents provide the first opportunity to both selectively and substantially reduce Lp(a) levels; however, their ability to prevent cardiovascular events remains to be established.

In the current issue of European Journal of Preventive Cardiology, Kamstrup and colleagues present a comprehensive overview of the utility of Lp(a) measurements and factors involved in their performance. In doing so, they highlight important factors for consideration of how best to standardize and interpret measurements.⁷ Lp(a) demonstrates considerable genetic regulation, determining it’s number of Kringle repeats and isoform size, which in turn influences the rate of hepatic production and ultimately circulating concentrations. A modest degree of modulation of circulating Lp(a) in the setting of inflammatory and chronic kidney disease implies the ability for intra-individual variability in systemic levels throughout life. Yet, as highlighted by the authors, there is an ongoing need to standardize analytical methods in order to produce uniform approaches to measurement and reporting of Lp(a) levels on samples, whether they have just been collected in the clinical setting or have been subjected to longstanding freezing, as often encountered in large cohort studies.

Why does this matter? An accurate account of the circulating concentration of Lp(a) is required to definitively elucidate its potential role in cardiovascular risk. While genomic tools such as Mendelian randomization are important, providing the information to infer potential causality, the strength of this tool depends on the ability to link genetic findings to clinical outcomes via an intermediate biomarker, in this case Lp(a) levels. Given the multitude of factors that influence Lp(a) production, the ultimate translation of a given genetic predisposition to apolipoprotein(a) [apo(a)] synthesis can result in variable circulating Lp(a) levels. This has potential implications for estimating the strength of relationship between a given increase in Lp(a) levels and cardiovascular risk in cohort studies. It has been recently reported that the increase in risk of atherosclerotic cardiovascular disease is substantially greater for each nmol/L increase in levels of Lp(a) compared with low-density lipoprotein (LDL) cholesterol.⁸ The relative validity of that comparison will be influenced by the ability to accurately quantify Lp(a) levels.

Accurate Lp(a) measurement has implications for understanding what is a sufficiently high enough level to associate with clinical risk and has implications for intensification of established preventive therapies. There is considerable interest in the use of Lp(a) as a risk enhancer in patients with familial hypercholesterolaemia, with the potential to influence the LDL cholesterol target for a given individual.⁹ It has also been reported that elevated Lp(a) levels associate with heart failure and peripheral arterial disease¹ and the strength of this relationship may differ in various disease states, again emphasizing the need for reliable Lp(a) quantitation. Given the potential for Lp(a) assessment to be of clinical utility in each of these settings, the ability to accurately quantify its concentration will become increasingly important.

The ability to use well-validated, standardized, and accurate Lp(a) assays also has implications for the setting of therapeutic Lp(a) lowering. Clinical trials have demonstrated efficacy of injectable RNA-interfering therapies that reduce apo(a) synthesis and more recently small molecule inhibitors that disrupt bonding of apo(a) to apolipoprotein B (apoB). The translation of gene editing to humans has the potential to also reduce apo(a) production. The ultimate question is whether Lp(a) lowering will reduce cardiovascular risk and what degree of Lp(a) lowering will be required to achieve this benefit? Large cardiovascular outcome trials will be required to answer these questions, but a reasonable sense of the relationship between a given degree of Lp(a) lowering and reduction in cardiovascular event rates will be required in study design. If these trials demonstrate clinical benefit, there will be efforts to understand the actual reduction in events per given degree of Lp(a) lowering and to compare these findings with additional LDL cholesterol lowering in these patients. Finally, with translation of effective therapies to the clinic, healthcare professionals may be faced with choices between agents with different levels of Lp(a) lowering and comparisons may be of importance in decision-making. Precise Lp(a) measurement will be essential to answer each of these questions.

The prominence of Lp(a) in cardiovascular prevention is undergoing considerable evolution. The near future has the potential to bring therapeutics that will transform our ability to lower Lp(a) in many patients, who currently have no effective treatment option. We need consensus on what is a clinically relevant high Lp(a) level, what degree of elevation will trigger more intensive use of preventive therapies, what level will trigger use of Lp(a)-lowering therapies, and how will we compare different agents in the clinic, presumably by a combination of their relative ability to lower both Lp(a) and cardiovascular risk. To achieve this setting, we will need Lp(a) testing that is accurate, standardized, inexpensive, and accessible to all patients. Given that most jurisdictions do not provide universal coverage for Lp(a) testing, this barrier will need to be overcome to provide more equitable approaches to integrating Lp(a) into cardiovascular prevention guidelines. While Lp(a) testing, in its current form, has played an important role to provide seminal insights into our understanding of Lp(a) and cardiovascular disease, better analytical approaches will be essential if we want to more effectively reduce cardiovascular risk.

Acknowledgements

S.J.N. has received research support from AstraZeneca, Amgen, Anthera, CSL Behring, Cerenis, Cyclarity, Eli Lilly, Esperion, Resverlogix, New Amsterdam Pharma, Novartis, InfraReDx, and Sanofi-Regeneron and is also a consultant for Amgen, Akcea, AstraZeneca, Boehringer Ingelheim, CSL Behring, Eli Lilly, Esperion, Kowa, Merck, Takeda, Pfizer, Sanofi-Regeneron, Vaxxinity, CSL Seqiris, and Novo Nordisk.

References

Author notes