Elevated Lipoprotein a – what are the treatment options?

12th December 2022, Dr Chee L Khoo

We explored lipoprotein a (Lp(a)) as a significant residual risk factor for atherosclerotic cardiovascular disease (ASCVD) and aortic stenosis in August this year. We looked at the strong and log-linear association between elevated Lp(a) and cardiovascular (CV) events. While the new PCSK9 inhibitors, notably alirocumab, has been shown to modestly reduce Lp(a) levels (and is associated with a small reduction in CV events) in the ODYSSEY trials, we do not have any agents that specifically lower Lp(a) approved yet (1). There are a number of agents in the pipeline, some in Phase 3 trials while others are going through Phase 1 and 2 trials. Reducing Lp(a) levels is one thing but does that reduce CV events? While we don’t have any agents that can substantially reduce Lp(a) levels, there are still a number of risks we can address while we await the new agents’ arrival. Let’s look at what we can do in the meantime.

Lp(a) metabolism

Lipoproteins are produced in the liver but it is unclear how lipoproteins are cleared from the circulation. From animal studies, it appears that the clearance of Lp(a) particles is achieved via the LDL receptor in the liver. In homo- or heterozygous familial hypercholesterolemia patients with a (total) loss of the LDL receptor, Lp(a) plasma levels is elevated, although this may be caused by selection bias (2). Statins do not lower Lp(a) but PCSK9 inhibitors do lower Lp(a), while both upregulate the LDL receptor. This suggests clearance largely independent of the LDL receptor pathway.

Kinetic studies have shown that apo(a) particles are excreted by the kidneys at a steady state. Early in the process of chronic kidney disease, apo(a) excretion is reduced and Lp(a) plasma levels increase (3,4).

Lp(a) levels are primarily genetically determined and are not influenced by lifestyle. Therefore, Lp(a) levels remain stable over life, in contrast to other cholesterol-carrying apoB particles such as low-density lipoprotein (LDL) particles. The Lp(a) plasma concentration is determined by two alleles of the LP(A) gene, coding for the apolipoprotein(a) molecule of the Lp(a) particle.

What is considered elevated Lp(a)?

Depending on the cut-off used, up to 20% of individuals worldwide have elevated Lp(a) plasma levels. Deciding what levels of Lp(a) is consider high is difficult as plasma levels of Lp(a) are highly dependent upon ethnicity [5]. In a recent analysis by Mehta et al. in the MESA (Multi-Ethnic Study of Atherosclerosis), black participants had a median Lp(a) level of 35.2 mg/dl, much higher than white, Hispanic, or Chinese participants (median 13.2 mg/dl) [6]. Despite the racial differences, the ASCVD risk resulting from Lp(a) seems largely similar across different ethnicities [5].

In general, increased risk is suggested to occur > 75 – 125 nmol/L. Your local pathology provider may have a different set of units and range.

Lp(a) and ASCVD and Aortic Stenosis

In one of the Mendelian randomization analyses by the group of Ference, it was shown that every 10 mg/dl (21 nmol/l) Lp(a) increase above median is associated with a 5.8% relative risk increase for coronary artery disease [6]. Elevated Lp(a) is also associated with a high risk of ischaemic stroke and heart failure as well as with cardiovascular and all-cause mortality, albeit with a smaller effect size.

For patients with an Lp(a) above the 95th percentile compared to low levels, the HRs for ischaemic stroke, cardiovascular mortality, and all-cause mortality were 1.6X, 1.5X and 1.2X respectively. In the same population, the HR for calcific aortic valve disease in patients with Lp(a) levels above the 95th percentile is 2.9 X [8].

Mechanisms of damage?

Lp(a) particle contains apoB and may therefore, have similar atherogenic properties as other apoB particles such as LDL-C, although the absolute concentration of Lp(a) particles is usually much lower in comparison with LDL-C. Lp(a) not only is the carrier of LDL-C, it is also the main carrier of oxidised phospholipids (e.g. ceramides). These phospholipids are recognised as damage-associated molecular patterns and therefore can result in pro-inflammatory as well as pro-calcific effects (in aortic valve stenosis). It is postulated that the apolipoprotein(a) part selectively binds to endothelial extracellular matrix proteins and thereby can be retained in the arterial wall [9]. The apolipoprotein(a) part is largely similar in structure to plasminogen which is thrombotic and may interfere with fibrinolysis.  

Who should we test?

As to the question of who we should be testing Lp(a) levels on can be a bit tricky. We could order an Lp(a) level for all patients whom we are organising a blood test for. After all, in the ESC 2020 guidelines on management of hyperlipidaemia, they recommend “Lp(a) measurement should be considered at least once in each adult person’s lifetime to identify those with very high inherited Lp(a) levels >180 mg/dL (>430 nmol/L) who may have a lifetime risk of ASCVD equivalent to the risk associated with heterozygous familial hypercholesterolaemia”. This is kind of screening everyone.

But then they also recommend “Lp(a) should be considered in selected patients with a family history of premature CVD, and for reclassification in people who are borderline between moderate and high-risk” (10). This is a little more targeted.

Routine measurement of Lp(a) is not yet recommended in Australia.

Treatment of elevated Lp(a)?

While moderate- to high-intensity statins lower plasma LDL-C for 50% by upregulating the LDL receptor, statins do not lower plasma Lp(a) levels. In fact, a recent meta-analysis of 6 RCTs involving 5256 patients showed that statins significantly increased plasma Lp(a) levels by 11.6% to 24.2% compared to placebo [11). However, a much larger meta-analysis including 24,448 data from 39 placebo controlled RCTs showed no significant effect of statin treatment on Lp(a) plasma levels [12]. Therefore, it does not seem likely that plasma Lp(a) is affected in a clinically meaningful manner by statin therapy. Besides, the benefit from reducing LDL-C overwhelmingly outweigh and potential increase in Lp(a) in patients on statin therapy.

Ezetimibe additionally lowers apoB and LDL-C plasma levels up to 20%, ezetimibe seems to have no or a very small effect on plasma Lp(a) levels. Both as monotherapy as well as in addition to statin therapy, ezetimibe had no effect on plasma Lp(a) concentration in a meta-analysis of 10 placebo-controlled randomised controlled trials (RCTs) including 5188 participants [13].

A third oral lipid lowering drug, bempedoic acid lowers apoB and LDL-C by approximately 20%, depending on the combination of lipid lowering therapies prescribed [14]. Bempdeoic acid was approved by the US FDA and European Medicine Agency in 2020 for the treatment of hypercholesterolemia in combination with diet and the highest tolerated statin therapy in adults with heterozygous familial hypercholesterolemia, or with established atherosclerotic cardiovascular disease, who need additional lowering of LDL cholesterol. There is no data available on the effect of bempedoic acid on Lp(a) levels. Bempedoic acid is not available in Australia.

Both the PCSK9 inhibiting monoclonal antibodies, Alirocumab, Evolocumab and their sister compound, the small interfering RNA (siRNA), Inclisiran have been shown to decrease Lp(a) levels by 25-27%. It is thought that reduction in Lp(a) is likely due to the fact that Lp(a) is metabolised by LDL receptors in the liver. An increase in LDL receptors by PCSK9 inhibitors action will increase the metabolism of Lp(a).

Pelacarsen (TQJ230) is an N-acetylgalactosamine (GalNAc3) conjugated antisense oligonucleotide targeting apolipoprotein(a) mRNA. The phase I/IIa trial proved pelacarsen to be safe and well-tolerated in 64 participants while reducing Lp(a) plasma levels [15]. The subsequent dose-ranging RCT in 286 patients with established ASCVD again showed a mean 80% reduction in plasma Lp(a) levels [16]. The Lp(a)- HORIZON cardiovascular outcome trial have fully enrolled 7680 patients with established ASCVD and due to report in 2025.

Olpasiran is an siRNA agent specifically targeting LP(A) mRNA. In the phase I trial in 64 healthy adults, Lp(a) was persistently reduced up to 90% without major safety issues [17]. Phase 2 is expected to be completed by the end of 2023.

SLN360 is another siRNA agent that has just completed its Phase 1 trial demonstrating that it is well tolerated and reduce Lp(a) by 98%.

Nurmohamed et al. Current Atherosclerosis Reports (2022) 24:831–838

Who should we treat?

While we await Lp(a)-HORIZON CVOT to report towards the end of 2025, “treatment” consist of relooking at the patient’s CV risk assessment if Lp(a) is elevated. In patients who may otherwise be deemed as intermediate or higher CV risk, an elevated Lp(a) may warrant initiation of a statin +/- ezetimibe +/- PCSK9i +/- aspirin. If the revised CV risk is now considered high or very high, then the target of LDL-C might have to be revised lower. Perhaps, an LDL-C target of 1.4 mmol/L or lower might now be necessary.

While the US Preventative Services Task Force does not recommend aspirin for primary prevention, a discussion and exploration of the pros and cons of aspirin might be necessary for the patient in front of you. If the bleeding risk is not high or can be mitigated, aspirin for prevention of CV events might be a consideration. This is especially the case, if the patient’s Lp(a) is elevated.

Perhaps, a coronary artery calcium score might come handy to augment the discussion with that patient. We shall explore CAC in the next issue of GPVoice.

References:

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