Understanding Lipoprotein(a)

In recent decades, lipoprotein(a) [Lp(a)] has emerged as an independent risk factor for atherosclerotic cardiovascular disease (ASCVD) [1]. Its measurement has since been incorporated into cardiovascular guidelines globally [2-4].

To facilitate understanding of the clinical utility of Lp(a) and its association with cardiovascular risk, Roche Diagnostics hosted a webinar on 1 November 2023. The webinar featured presentations from Prof Steven Nicholls, Program Director at Victorian Heart Hospital, A/Prof David Sullivan, Clinical Associate Professor at Sydney Medical School, University of Sydney, and A/Prof Karam Kostner, Director of Cardiology at Mater Hospital in Sydney.

Elevated Lp(a) is an independent and causal risk factor for atherosclerotic cardiovascuar disease (ASCVD)

- Australian Atherosclerosis Society

Lipoprotein(a) is prominently associated with risk of cardiovascular disease

The higher an individual’s Lp(a) levels, the higher their risk of early cardiovascular disease (CVD), myocardial infarction and coronary death [1, 5, 6]. Approximately 30-50% of individuals with familial hypercholesterolaemia (FH) are also found to have elevated Lp(a) levels [7]. The CVD risk conferred by Lp(a) elevation persists across ethnic groups, despite racial variation in Lp(a) levels [8].

Various studies have investigated the association between CVD risk and LP(a). Mendelian randomisation has demonstrated the causal role of Lp(a) in ASCVD and the subsequent usefulness of Lp(a) as a target for cardiovascular (CV) therapies [9]. Recent large randomised controlled trials for lipid lowering therapies, such as the AIM-HIGH [10] and JUPITER studies [11], have also found an association between elevated Lp(a) levels and residual CVD risk [12]. Data from genomic studies not only indicate the CV risks associated with Lp(a) but indicate that Lp(a) lowering can reduce CVD risk [9]. However, Prof Nichols indicated that this requires confirmation through clinical outcome studies, which “becomes important for the design of clinical trials moving forward”.

The importance of lipoprotein(a) measurement for personalised treatment

Elevated Lp(a) is highly prevalent. Approximately 20% of the global population have elevated Lp(a) levels [13]. This, alongside its association with CVD risk, signifies the potential clinical utility of Lp(a), and the subsequent importance of Lp(a) measurement [2-4].

However, the high structural variability of Lp(a) complicates its measurement. Historical assays based on mass would subsequently miscalculate the amount of Lp(a). Because of this, modern size-calibrated polyclonal immunoassays calculate Lp(a) concentrations in molar units instead of mass units [13, 14]. Consensus statements from both the European [2] and Australian Atherosclerosis Society [3] recommend the measurement of Lp(a) with a size independent assay, in molar units.

Circulating Lp(a) concentrations should have estimated using an apo(a)-isoform independent assay that employs appropriate calibrators and reports the results in molar units (nmol/L).

- Australian Atherosclerosis Society

The Australian Atherosclerosis Society recommends selective screening strategies be implemented when measuring Lp(a). Lp(a) should be measured in all patients with premature ASCVD and those considered to be at intermediate-high risk of ASCVD [3, 15]. A/Prof Kostner explained that the elevation of Lp(a) can then be used to assess and stratify the patient’s CVD risk leading to initiation or intensification of preventative treatment [3].

Lp(a) testing in clinical practice has the potential to recharacterize the risk, and therefore optimise treatment, of up to 40% of conventionally classified intermediate-risk patients, as noted by Prof Nicholls [16]. For intensive treatment of patients with Lp(a) correlating to a high CVD risk, A/Prof Kostner particularly recommended aggressive reduction of low-density lipoprotein with statins, ezetimibe and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors.

For the clinical utility of Lp(a) to be seen in practice, widespread access to Lp(a) testing is needed.

Current and emerging therapies for the management of elevated lipoprotein(a)

Therapies that lower Lp(a) are currently used in clinical practice [17, 18].

In large clinical outcome trials of PCSK9 inhibitors such as alirocumab, Lp(a) lowering appears to correlate to a reduction of CV risk [19]. “This leads to thoughts about new therapies coming down the line, which have been specifically designed to directly target Lp(a)” Prof Nicholls said.

Emerging therapies primarily target Lp(a) production in the liver by targeting Lp(a) RNA.

These include antisense RNA therapy, which reduced Lp(a) by75-80%, RNA interference therapy which reduces Lp(a) by approximately 90%, and RNA silence therapies such as olpasiran [20-22] which can reduce Lp(a) by approximately 98%. Oral treatments are also in development. Muvalaplin is a small molecule Lp(a) inhibitor that prevents binding between the apolipoproteins in Lp(a), reducing levels by 65%. Cholesterylester transfer protein (CETP) inhibitors such as obicetrapib [23, 24] can also reduce Lp(a) by 30-50%. Gene editing is also emerging as an approach to treating low density lipoprotein cholesterol, with non-human primate data showing promising results [25]. This may be utilised in the future to target the Lp(a) gene, Prof Nicholls noted.

A/Prof Kostner noted that, aside from infusion related reactions, therapies targeting Lp(a) appear to be well tolerated. A/Prof Sullivan explained that ... “Mendelian randomisation can predict if a therapy will have side effects.” He said that, as Lp(a) is not widely distributed in nature, it is expected that lowering it would have few side effects.

These emerging therapies require evaluation in CV outcome trials to determine any reduction in CV risk, directly related to a reduction in Lp(a). With further evidence, practice will evolve from therapies that have a limited effect on Lp(a), to much more effective oral small-molecule or injectable treatments, Prof Nicholls concluded.

Future considerations for the clinical utility of lipoprotein(a)

Lp(a) is a highly important area for development in CVD. “Lp(a) is the first independent CVD risk factor within the last two or three decades and is exemplar of precision medicine via mendelian randomisation,” A/Prof Sullivan highlighted.

As emphasised by Prof Nicholls, future management of CVD will depend on evidence from large clinical outcome trials, and effective biomarkers to identify prominent risk factors such as Lp(a), to allow personalised treatment. Investigation of Lp(a) in clinical outcomes trials is vital for important considerations, such as: what a clinical meaningful reduction of Lp(a) is; why Lp(a) is produced in the body; and subsequently, if there are any long-term consequences of Lp(a) lowering agents. A/Prof Sullivan emphasised that, until Lp(a) lowering agents are proven to be safe and effective, Lp(a) must be regarded as an important means of nuancing risk in the intermediate category of ASCVD. A/Prof Sullivan said. “We should not think about other biomarkers until we have done a good job sorting out Lp(a). It may do just about everything we need.”

To learn more about lipoprotein(a), watch the full webinar here, with Prof Nicholls, A/Prof Sullivan and A/Prof Kostner.

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Click here to download this article as a pdf "Lipoprotein(a): The Science Behind the Risk Factor"

References

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