What is Lp(a)?

It is another “atherogenic lipoprotein”. Think of Lp(a) as an LDL particle (cholesterol-rich lipoprotein) with an apolipoprotein (a) covalently bound to apolipoprotein B by a disulfide bridge.

Apo(a) is produced in the hepatocyte (liver cell). Apo(a) size is highly variable due to something called “Kringle repeats”. There are multiple Kringle (looks like a molecular Kringle Danish pastry) repeat domains (K1-KX) within Apo(a). In particular, within the domain KIV₂there may be just a few or multiple copies, which determines the size of the particle. There is an inverse relationship with the amount of KIV₂ repeats, whereupon less repeats are associated with greater number of particles. More repeats produce large particles, which produces less expression. Levels can vary up to 1000 fold between individuals.

The Apo(a) gene accounts for 90% variability.

Awareness

Despite its discovery in 1963 by Norwegian scientist Kare Berg, we are only beginning to understand Lp(a) and develop direct therapies against it (Ionis Pharmaceuticals). Not everyone wants to know every genetic condition they may be at risk for (like with whole genome sequencing Illumina), particularly if nothing can be done about it. But high Lp(a) is neither rare, nor without disease altering treatments.

Perhaps if Bob Harper were not otherwise so healthy, his disease might have presented sooner or been more advanced by the time it manifested. Perhaps. He certainly was doing all he could to stave off heart disease.

Conversely, with increased attention to awareness, it may be possible to detect disease before it manifests (A Picture is Worth a Thousand Words - Coronary Artery Calcium Scores), particularly in otherwise healthy athletes who may encounter “healthy athlete bias” (Killer Workouts - The Adult Athlete). Additionally, starting a statin to reduce ApoB, which represents other atherogenic particles for which there are a number of safe and effective therapies, may have prevented

What should not be the message here is what unfortunately some of the social media fallout concluded: “what’s the point of exercising and eating healthy if it makes no difference?” This sort of nihilistic impression is eerily similar to the reaction to the death of Jim Fixx.

Rather, we need to continue to raise awareness around both “modifiable” and “non-modifiable” risk factors. They are not mutually exclusive.

Atherogenic:

While the Lp(a) is an LDL-like particle, capable of trafficking cholesterol esters and infiltrating the endothelial wall, it’s felt that the majority of its contribution to atherosclerosis is due to oxidized phospholipids contained on its polar membrane. Pound for pound oxidized phospholipids appear to contribute more to the inflammatory process due to cell signaling rather than plaque accumulation.

Oxidized phospholipids, pound for pound, may contribute even greater to plaque inflammation. This may explain the enhanced atherogenicity of Lp(a) particles, despite the relatively small numbers when compared to LDL particles. In this study Lipoprotein(a) Is Markedly More Atherogenic Than LDL: An Apolipoprotein B-Based Genetic Analysis, Lp(a) is about 6 times more atherogenic.

As for its ApoB contribution, there is a 1:1 relationship of apoB to Lp(a). If the Lp(a) is 125 nmol/L, this means the apoB is also 125 nmol/L. Dividing 125 nmol/L by the conversion factor 19.49 gives an apoB of 6.4 mg/dL, which is the concentration of apoB attributable to Lp(a) in this scenario. But even in the setting of low LDL-C (ApoB), very high Lp(a) remains a risk factor.

It is also homologous to plasminogen (see below), and therefore felt to mimic the ability of plasminogen to bind fibrin at sites of blood vessel damage, which increases cholesterol delivery.

Thrombogenic:

Apolipoprotein (a) is a protein sequence with regions closely related (homologous) to plasminogen. Plasminogen breaks down clot (thrombolysis). Lp(a) may therefore compete for the binding sites of plasminogen. The body requires “homeostasis” (Goldilocks - not too little, not too much). It’s thought that in those individuals with high levels of Lp(a), it may be interfering with plasminogen and therefore poses a greater risk of promoting clot in the setting of a plaque rupture.

Plaque rupture is the most common mechanism for heart attack. Like a zit on a teenager’s face, that pimple in the artery wall is being contained by a fragile endothelial “cap”. When that “cap” finally breaks down (with the help of matrix metalloproteinases and other inflammatory mediators) due to the relentless effects of inflammation (driven by ApoB containing lipoproteins) it fissures, or ruptures and releases Tissue Factor and other highly thrombogenic compounds into the artery lumen, activating thrombin, which then activates platelets and triggers the coagulation cascade. If all those stars align, then just like a snowball rolling down the mountainside, a large sticky clot forms and either instantly and completely clogs up the artery, or it might break into multiple smaller clots that are showered downstream and eventually get trapped in smaller artery branches. Either can cause a heart attack (death of heart muscle tissue), but if in the former, that large clot happens to get stuck high up in the LAD (“widowmaker”), blood flow instantly stops flowing and that large area of heart muscle living downstream is suddenly deprived of oxygen and nutrients. The heart (left ventricle) instantly fibrillates and the person dies (V-fib arrest). That’s sudden cardiac death. It occurs in 50% of those suffering their first heart attack.

Doesn’t all plaque rupture cause a heart attack? No, not always. IVUS (intravascular ultrasound) and OCT (optical coherence tomography) are technologies where a wire is advanced along a vessel and is capable of visualizing plaque volume, morphology and other characteristics. We have seen evidence of previous plaque rupture in multiple stages of healing, without any clinical evidence of prior heart attack. In fact, for large plaque (>70% - enough to flunk a stress test by invoking ischemia), it’s likely that the plaque has ruptured and healed and ruptured and healed and the person was never the wiser. For whatever reason, the stars didn’t align. A large enough clot didn’t develop.

But the fear for those with very high Lp(a), is that when they rupture a plaque, they do it big time and that snowball builds fast and plasminogen (which breaks down or prevents clot) is being “stiff armed” by Lp(a). Therefore, the ASCVD event (stent, bypass, stroke, heart attack, PAD) in patients with high Lp(a) are more likely to be of a “thrombotic” variety - meaning heart attack or stroke. They also tend to be “premature”, or earlier in life. That plaque rupture is just not as likely to occur silently and without clinical consequence.

Inheritability:

If Lp(a) is so bad, why is it so inheritable? Lp(a) is found in humans, Old World nonhuman primates and the European Hedgehog. In prehistoric people it may have promoted wound healing at sites of vessel injury. In modern people it accelerates atherosclerosis (and calcific aortic stenosis).

Current Treatments for Lp(a) associated Risk:

Presently, all we can do to mitigate the additional risk imparted by an elevated Lp(a) is to target the risk factors for ASCVD for which we do have substantial evidence for risk reduction and to do so more aggressively than we might otherwise.

Therapies Not Recommended for Lp(a) Lowering:

Niacin does lower Lp(a), however this drug has a number of off-target effects and has fallen out of favor after 2 important clinical trials failed to show any clinical benefit. In 2011 the NHLBI-funded AIM-HIGH trial was published and showed no clinical benefit beyond statins in those with ASCVD despite improvements in HDL-C (not surprisingly as we discuss elsewhere in What's Your ApoB? A Practical Approach to Lipid Management: (Hint: “It's the particles, stupid”)) and triglycerides. Soon after, in 2014, HPS2-THRIVE trials showed no clinical benefit beyond statin therapy but did demonstrate significant side effects to include diabetes control (most leading to hospitalization), new onset diabetes, gastrointestinal upset, musculoskeletal (myopathy - 10 times higher in the Chinese participants), skin irritation and unexpectedly - infection and bleeding. These 2 trials put the nail in the coffin for Niacin and it is no longer recommended as a lipid lowering agent. Furthermore, the modest impact on Lp(a) particle number may not be enough to derive a clinical benefit. Therefore, one runs the risk of no clinical benefit and exposure to the plethora of side effects attributed to this drug.

Estrogen also modestly lowers Lp(a), but again, to the degree that Lp(a) is lowered, there may be no significant clinical benefit to offset the potential side effects of hormone replacement therapy for this indication.

PCSK9 inhibitors and Lp(a):

While PCSK9i do in fact lower Lp(a), they are not approved for Lp(a) lowering. There were some favorable subgroup analysis data from the FOURIER (Lipoprotein(a), PCSK9 Inhibition, and Cardiovascular Risk | Circulation) and ODYSSEY OUTCOMES (Lipoprotein(a) lowering by alirocumab reduces the total burden of cardiovascular events independent of low-density lipoprotein cholesterol lowering: ODYSSEY OUTCOMES trial), where those at the highest levels of baseline Lp(a) had a greater absolute risk reduction compared with those with the lowest Lp(a) levels. Questions remain regarding linear reductions in Lp(a) and ASCVD risk versus a significant large threshold reduction in Lp(a) to achieve any risk reduction.

Future Therapies Directly Targeting Lp(a) :

There are many promising treatments directly targeting LP(a) currently in development, to include Phase III clinical trials. Ionis Pharmaceuticals.

These treatments are small molecules such as siRNA (small inhibiting RNA) or ASOs (antisense oligonucleotides). In review, messenger RNA (mRNA) is a piece of single stranded RNA genetic data transcribed from our DNA, which is then translated by ribosomes to form a particular protein (made up of amino acids), which are what ultimately carry out certain functions in our bodies.

In the case of Lp(a), small molecule therapies derived from siRNA and ASO inhibit the ribosome from “reading” the LPA gene and “manufacturing” apolipoprotein(a), which means Lp(a) is not formed. This results in dramatic reductions in Lp(a) particle number.

Safety and efficacy trials have already concluded that these agents safely reduce Lp(a) without signal of harm. However long term clinical outcomes trials, which take years, have been hampered by enrollment during the COVID epidemic and are awaiting completion.

In the case of LDL lowering, the FDA acknowledges that the causal agent in atherosclerosis is ApoB containing lipoproteins - predominantly LDL, which is therefore considered an acceptable surrogate for atherosclerosis. Historically, treatments that safely and effectively lower LDL-C, such as statins, ezetimibe, PCSK9i, bempedoic acid were given FDA approval without necessarily completing cardiovascular outcomes trials prior to approval (though positive CV outcomes trials have now been published for each of these classes of drugs).

When it comes to Lp(a), however, it remains unknown whether Lp(a) lowering therapies reduce ASCVD risk. Mendelian Randomization Trials suggest that it may require substantial Lp(a) lowering (> 50-100 mg/dL) to result in ASCVD risk reduction. CV outcomes trials are therefore necessary to establish whether a given drug, resulting in a given reduction in Lp(a) levels, on top of established LDL lowering and other therapies, will provide additional benefit.

Specific Drugs in Development:

Pelacarsen | Ionis Pharmaceuticals, Inc.: Antisense oligonucleotide (ASO) aimed at inhibiting production of apolipoprotein(a). Pelacarsen reduces apo(a) ~ 80%. The Lp(a)HORIZON Phase 3 cardiovascular clinical outcomes trial has completed enrollment and is scheduled to be completed spring 2025.

Olpasiran (AMGEN) is a small interfering RNA (siRNA) which has shown 101% reduction in Lp(a) levels in a dose finding study called OCEAN(a)-DOSE Trial published in the New England Journal of Medicine. The Phase 3 OCEAN (a) Outcomes trial is currently recruiting and on course for completion 12/31/2026.

Zerlasiran from Silence Therapeutics is a siRNA which has completed Phase 1 clinical trial (NCT04606602)

LY3819469 (Eli Lilly) is a siRNA in Phase 2 trials: A Study of LY3819469 in Participants With Elevated Lipoprotein(a) [Lp(a)].