Lipoprotein(a): The Overlooked Particle That Most Cholesterol Tests Miss

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It’s called Lipoprotein(a), or Lp(a) for short. And if you haven’t had it measured, you’re not alone—most people haven’t.

In fact, most of you may have never heard of it.

It’s not part of a standard lipid panel. It doesn’t show up in routine check-ups. And yet, one in five people carry levels so high they double or triple their risk of a heart attack or stroke—even if their cholesterol is “normal.”

This isn’t the first time I’ve written about Lp(a).
Back in 2021, I published an earlier version of this article to spotlight a neglected piece of the cardiovascular puzzle. But now, the landscape is shifting.
Trials are underway. Guidelines have evolved. And for the first time, therapies built specifically to lower Lp(a) are on the horizon.

Because Lp(a) is no minor footnote in cardiovascular risk.
It’s a genetically determined, cholesterol-rich particle with a nasty habit of promoting plaque buildup, clot formation, and aortic valve calcification. It doesn’t respond to statins. Diet won’t touch it. And for decades, there was nothing we could do about it.

Now, that’s changing.

This updated article explores what Lp(a) is, how it causes harm, who should get tested, and why we may need to rethink what we mean by “normal” cholesterol.

The Lipoprotein That Got Left Behind’

For decades, Lp(a) hovered at the edge of cardiovascular medicine—known, but mostly ignored.

It wasn’t that scientists hadn’t noticed. Lp(a) was first described in 1963. Its structure, risk associations, and biochemical quirks have been studied for years.

But there were obstacles.

No routine test.
No insurance coverage.
No treatments.
No mention in the guidelines.

So while LDL (Low-Density Lipoprotein) was measured and managed down to decimal precision, Lp(a) remained an academic curiosity—important in theory, irrelevant in practice.

Doctors didn’t order it. Labs didn’t report it.
And when it did show up? There was nothing to do.

In a medical culture built around action, a risk factor with no remedy is easy to overlook. And that’s exactly what happened.

That’s changing.

Today, Lp(a) tests are widely available and standardized in nanomoles per liter (nmol/L).

Major heart health organizations—including the American Heart Association (AHA), American College of Cardiology (ACC), and European Society of Cardiology (ESC)—now recommend testing every adult at least once, especially those with a family history of early heart disease or stroke.

And for the first time, we have experimental drugs that target Lp(a) directly, reducing levels by up to 90% in trials.

The result?

Lp(a) is no longer an orphan metric.
It’s moving to center stage—not just as a marker, but as a modifiable, causal factor in cardiovascular disease.

But there’s a catch.

Just because we can measure it—and even lower it—doesn’t mean we’ve solved the problem.

We still don’t know the most important thing of all:
Does lowering Lp(a) actually reduce cardiovascular events?

That’s the billion-dollar question.
And the answer won’t come from lab results. It will come from outcomes.

That’s why trials like HORIZON and OCEAN(a) matter so much.
They’re not just testing new drugs.
They’re testing the idea that modifying one number can change real-world risk: heart attacks, strokes, valve replacements, lives saved.

Until we have that data, Lp(a) remains causal, measurable, and promising—but not yet proven in clinical endpoints.

Structure of Lipoprotein(a): This diagram illustrates the key components of lipoprotein(a), or Lp(a). The particle consists of a cholesterol-rich core, a surrounding apoB-100 protein (blue), and an additional apo(a) tail (green and yellow) linked by a disulfide bond (S-S). Oxidized phospholipids (OxPL) are attached to apo(a), contributing to the pro-inflammatory and atherogenic properties of Lp(a).

What Is Lipoprotein(a) – Why Is It So Dangerous?

At first glance, Lipoprotein(a) looks like LDL.

It carries cholesterol through the blood. It contains one molecule of apolipoprotein B100 (apoB). And like LDL, it’s atherogenic—capable of sneaking into artery walls and fueling plaque buildup.

But Lp(a) has a hidden weapon: a strange, sticky appendage called apolipoprotein(a)—apo(a) for short.

This tail-like structure is what makes Lp(a) different—and dangerous.

The Molecular Double Life

Apo(a) is structurally similar to plasminogen, a protein that helps break down blood clots. But unlike plasminogen, apo(a) can’t dissolve anything. In fact, it may compete with plasminogen for binding sites, inhibiting the body’s ability to clear clots.

That gives Lp(a) a double dose of danger:

  • It promotes atherosclerosis like LDL.
  • And it may enhance thrombosis like a clotting factor gone rogue.

But that’s not all.

Lp(a) is also a major carrier of oxidized phospholipids (OxPLs)—inflammatory molecules that accelerate endothelial dysfunction, arterial calcification, and plaque vulnerability.

Lp(a)’s unique biology also promotes valve calcification, particularly in the aortic valve—making it one of the few known lipoproteins directly implicated in both atherosclerosis and valvular heart disease.

LP(a) Is LDL – With a Hidden Load

Here’s something most lab reports don’t tell you:

Lp(a) cholesterol is included in your LDL-Cholesterol (LDL-C) measurement.

Because Lp(a) is, by definition, an LDL particle with an apo(a) tail, its cholesterol content is lumped into the LDL-C number reported on standard lipid panels.

That matters—especially in patients with high Lp(a). In fact, 10–30 mg/dL of your LDL-C may come from Lp(a) if your levels are elevated.

This has two major clinical implications:

  1. After statin therapy, what’s left may be disproportionately Lp(a)-rich LDL-C—unchanged by the drug.

  2. Residual cardiovascular risk may remain, even if LDL-C is “at goal.”

This is one reason why ApoB and non-HDL-cholesterol are more reliable risk markers than LDL-C alone—especially in patients with elevated Lp(a).

How Much Is Too Much? Lp(a) Levels and Cardiovascular Risk

One of the challenges with Lp(a) is that patients often have no idea what their number means—even if they’ve had it tested. The reference ranges vary by lab, and to make things more confusing, two different units are used:

  • nmol/L — particle concentration (preferred by most experts)

  • mg/dL — mass concentration

The same person might have an Lp(a) level of 120 nmol/L or 50 mg/dL, and both mean the same thing: high risk.

What Patients Should Know
  • There’s no clearly defined “safe” level of Lp(a)—but risk tends to rise as levels increase.
  • Lp(a) is genetically determined. Lifestyle changes have minimal effect.
  • It’s not part of a standard cholesterol panel. You have to ask for it.
  • Most people only need to measure it once, unless their risk profile changes or new treatments become available.

When Lp(a) Testing Should Be Considered

  • Personal history of early heart disease or stroke
  • Strong family history of cardiovascular disease
  • High calcium score or residual risk despite normal LDL
  • Unexplained aortic valve stenosis
  • Recurrent events on statins

High Risk, Not a Death Sentence

If you’ve just learned that your Lp(a) is high—say, over 125 or even 200 nmol/L—it’s natural to feel uneasy. But here’s an important truth:

Elevated Lp(a) increases risk. It does not guarantee disease.

In fact, many people with Lp(a) levels well above 200 nmol/L never develop atherosclerosis or valve disease, even into older age. How is that possible?

Because Lp(a) is just one piece of a much larger puzzle.

Atherosclerosis Is multifactorial

Whether or not someone develops plaque depends on the total burden of atherogenic lipoproteins, metabolic factors like insulin resistance or hypertension, and the presence of inflammation, smoking, or other pro-atherogenic conditions.

Some people inherit high Lp(a) but also:

  • Have low ApoB
  • Maintain excellent metabolic health
  • Show no coronary calcium on CT
  • And never develop clinical disease

There are also likely genetic modifiers and protective mechanisms we don’t yet fully understand. Lp(a) may be present, but not particularly active or harmful in every individual.

Clinical Implication

This is why context is everything.

Testing Lp(a) is crucial, but it’s not the whole story. If your Lp(a) is high, your doctor should interpret it alongside:

  • ApoB and LDL-C
  • Blood pressure and glucose markers
  • Calcium score (if applicable)
  • Family history and clinical risk

Think of Lp(a) as a lens—not a verdict.

It helps reveal hidden risk in some patients, but in others, it may simply be background noise.

What Can Be Done About It?

For years, the answer was simple—and frustrating: not much.

Unlike LDL-C or triglycerides, Lp(a) doesn’t budge with diet, exercise, or weight loss. It’s a genetic trait—more like eye color than blood sugar. But that doesn’t mean it should be ignored. In fact, being aware of it can alter how we manage the rest of our risk profile.

Still, it’s worth asking: can anything bring Lp(a) down?

Existing Therapies: Modest and Indirect

Statins

While statins reliably reduce LDL-C and ApoB, their effect in patients with high Lp(a) is less clear. In fact:

  • May slightly increase Lp(a) levels (by ~10–20% in some studies)
  • Still reduce LDL-C, ApoB, and overall cardiovascular risk in most populations
  • However, their benefit in patients with high Lp(a) is uncertain—this subgroup has not been well studied in major statin trials
  • For now, statins remain standard care when ApoB is elevated, but in patients with high Lp(a), they may be necessary but not sufficient, and possibly less effective
PCSK9 Inhibitors (e.g., evolocumab, alirocumab)
  • PCSK9 inhibitors lower Lp(a), but whether this reduction has clinical significance is still an open question.
  • Lower Lp(a) by approximately 20–25%, in addition to robust LDL-C and ApoB reduction
  • No trial to date has shown that lowering Lp(a) with these drugs improves outcomes independently
  • Subgroup analyses (e.g., from FOURIER) suggest greater relative benefit in patients with high Lp(a), but this is exploratory
  • May be reasonable in high-risk patients where both LDL-C and Lp(a) are elevated—but this is extrapolated, not evidence-based
Niacin
  • Can reduce Lp(a) by 20–30%
  • Not recommended in routine practice due to lack of benefit in outcome trials and frequent side effects (e.g., flushing, hepatotoxicity, glucose intolerance)
  • Major trials (AIM-HIGH, HPS2-THRIVE) showed no reduction in heart attack, stroke, or mortality, despite lipid changes.
Even without a specific drug, knowing a patient’s Lp(a) level can change management:
  • More aggressive LDL-C or ApoB targets
  • Use of PCSK9 inhibitors in high-risk patients
  • Intensified control of other modifiable risks (blood pressure, glucose, inflammation)
  • Screening family members if Lp(a) is very high

In short: Lp(a) testing doesn’t end the conversation—it reframes it.

The Race to Treat Elevated Lp(a): HORIZON and OCEAN(a)

Two agents are in late-stage trials: Pelacarsen (antisense oligonucleotide) and Olpasiran (siRNA)

These drugs target apo(a) synthesis in the liver—essentially switching off the gene responsible for excess production.

If these ongoing trials show a reduction in cardiovascular events, we could see regulatory approval by 2025–2026.

For the first time, we may have medications designed not just to treat cholesterol, but to neutralize a genetically programmed risk.

HORIZON: Targeting Lp(a) with Antisense Technology

The HORIZON trial is a phase III study evaluating pelacarsen (also known as TQJ230).

In phase II studies, pelacarsen reduced Lp(a) by up to 80% with a favorable safety profile.

HORIZON is enrolling over 8,000 patients with established atherosclerotic cardiovascular disease (ASCVD) and elevated Lp(a) (>70 mg/dL).

The goal: determine whether Lp(a) reduction translates into fewer major cardiovascular events (MI, stroke, cardiovascular death).

Results are expected in 2026.

This trial is more than a test of a new drug. It’s a test of causal inference—if lowering Lp(a) reduces events, it confirms that Lp(a) isn’t just a marker. It’s a culprit.

OCEAN(a): Going Deeper with siRNA

The OCEAN(a)-Outcomes trial is a global phase III study of olpasiran, a small interfering RNA (siRNA).

In early-phase trials, olpasiran achieved >90% reductions in Lp(a)—more potent than any agent to date.

Like HORIZON, OCEAN(a) is enrolling patients with ASCVD and Lp(a) >200 nmol/L (~80 mg/dL).

The trial will test whether these deep reductions lead to fewer cardiovascular events.

Results are anticipated by late 2026 or 2027.

What’s striking is not just the magnitude of effect, but how specifically these drugs target Lp(a), independent of LDL-C, triglycerides, or HDL.

Epilogue: The Ghost in the Blood

David was 52.

He didn’t smoke. He exercised. His LDL was borderline. Blood pressure, fine. HbA1c, normal.

So when he had a heart attack, it came as a shock to him and to his doctor.

They called it a fluke. Put in a stent. Started a statin. Life moved on.

Two years later, it happened again.

But this time, someone looked deeper. A lipid specialist ran a broader panel.

Lp(a): 245 nmol/L. Off the charts. Unchecked. Unmentioned. Unmeasured.

It wasn’t part of his standard lipid test.
It wasn’t flagged as a risk factor.
But it had been there all along—a silent, genetically programmed threat.

He didn’t look like someone on borrowed time.

He looked like every other man in the waiting room—shirt tucked in, Apple Watch on his wrist, a clean cholesterol printout in his hand. But under the surface, a ghost had been moving quietly for years.

That’s the reality for millions.
Not just the heart attack survivors, but the ones with unexplained strokes.
The ones with valve disease in their 50s.
The ones whose parents died too young.

This isn’t rare. It’s just rarely measured.

Now we have the tools to look—and soon, perhaps, the tools to treat.
Pelacarsen. Olpasiran. New names in a long-overdue war.

Not miracle cures. But a sign that medicine is catching up to what biology has always known:

Some people carry danger in their blood from the day they’re born.
And if we can find it early enough—we just might change the ending.

Related Reading on Doc’s Opinion

  • Non-HDL Cholesterol: The Hidden Heart-Disease Predictor You’ve Overlooked (link)
  • Atherogenic Dyslipidemia (link)
  • When High LDL Leads to Heart Disease — And When It Doesn’t (link)
  • The 12-Step Biology of Atherosclerosis (link)
  • The Triglyceride/HDL Cholesterol Ratio (link)
  • LDL-C vs. LDL-P: What’s the Difference? (link)
  • What’s the Best Lipid Marker to Predict Risk? (link)
  • Apolipoprotein B and Heart Disease (link)
  • High Triglycerides — And How to Lower Them (link)
  • VLDL, Triglycerides & Remnant Cholesterol (link)
  • HDL Cholesterol — The Good, the Misunderstood (link)
  • 10 Pitfalls of Using LDL-C to Assess Risk (link)
  • The Role of Low-Density Lipoprotein (LDL) in Atherosclerosis and Heart Disease (link)
  • LDL Particle Number vs. Size — Made Easy (link)
  • LDL-P (link)

References

  1. Tsimikas S. A Test in Context: Lipoprotein(a): Diagnosis, Prognosis, Controversies, and Emerging Therapies. J Am Coll Cardiol. 2017;69(6):692–711. doi:10.1016/j.jacc.2016.11.042. Link
  2. Nordestgaard BG, Chapman MJ, Ray K, et al. Lipoprotein(a) as a cardiovascular risk factor: current status. Eur Heart J. 2010;31(23):2844–53. doi:10.1093/eurheartj/ehq386. Link
  3. Boffa MB, Koschinsky ML. Lipoprotein(a): truly a direct pro-atherogenic particle. Curr Opin Lipidol. 2013;24(5):377–83. doi:10.1097/MOL.0b013e328363f6ab. Link
  4. Thanassoulis G, Campbell CY, Owens DS, et al. Genetic associations with valvular calcification and aortic stenosis. N Engl J Med. 2013;368(6):503–12. doi:10.1056/NEJMoa1109034. Link
  5. Tsimikas S, Karwatowska-Prokopczuk E, Gouni-Berthold I, et al. Lipoprotein(a) Reduction in Persons with Cardiovascular Disease. N Engl J Med. 2020;382(3):244–55. doi:10.1056/NEJMoa1905239
    → (Pelacarsen Phase II trial). Link
  6. Clarke R, Peden JF, Hopewell JC, et al. Genetic variants associated with Lp(a) lipoprotein level and coronary disease. N Engl J Med. 2009;361(26):2518–28. doi:10.1056/NEJMoa0902604. Link
  7. U.S. National Library of Medicine. HORIZON Trial (NCT04023552). ClinicalTrials.gov. Available at: https://clinicaltrials.gov/ct2/show/NCT04023552
  8. U.S. National Library of Medicine. OCEAN(a)-Outcomes Trial (NCT05581303). ClinicalTrials.gov. Available at: https://clinicaltrials.gov/ct2/show/NCT05581303
  9. Vinci P, Di Girolamo FG, Panizon E, Tosoni LM, Cerrato C, Pellicori F, Altamura N, Pirulli A, Zaccari M, Biasinutto C, Roni C, Fiotti N, Schincariol P, Mangogna A, Biolo G. Lipoprotein(a) as a Risk Factor for Cardiovascular Diseases: Pathophysiology and Treatment Perspectives. Int J Environ Res Public Health. 2023 Sep 6;20(18):6721. doi: 10.3390/ijerph20186721. PMID: 37754581; PMCID: PMC10531345. Link
  10. Khera AV, Everett BM, Caulfield MP, et al. Lipoprotein(a) concentrations, rosuvastatin therapy, and residual cardiovascular risk: an analysis from the JUPITER trial. Circulation. 2014;129(6):635–642. doi:10.1161/CIRCULATIONAHA.113.004406. Link
  11. Kamstrup PR, Tybjærg-Hansen A, Steffensen R, Nordestgaard BG. Genetically elevated lipoprotein(a) and increased risk of myocardial infarction. JAMA. 2009;301(22):2331–2339. doi:10.1001/jama.2009.801. Link
  12. Bittner V, Szarek M, Aylward PE, et al. Effect of alirocumab on lipoprotein(a) and cardiovascular risk after acute coronary syndrome. J Am Coll Cardiol. 2020;75(2):133–144. doi:10.1016/j.jacc.2019.10.057. Link
  13. Mehta A, Virani SS, Ayers CR, et al. Lipoprotein(a) and family history predict cardiovascular disease risk. J Am Coll Cardiol. 2020;76(7):781–793. doi:10.1016/j.jacc.2020.06.061. Link

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18 thoughts on “Lipoprotein(a): The Overlooked Particle That Most Cholesterol Tests Miss”

    • Hi Michael
      I’m not sure I agree.
      In theory, your coronary calcium score might have been higher than 362 if your Lp(a) was elevated.
      And, of course, many other factors are involved in the calcification of the coronary arteries.

      Reply

      • I’ve been getting my Lp(a) tested over the course of the last 8 years (went low carb/keto on 1/1/14), and my Lp(a) is ridiculously high over that time, between 220-360+ mmol/l, yet I got a zero score on CAC at about 5.5 year point. 90% of people had higher CAC scores (I was 55 at the time).

        I also have no aortic stenosis, as verified by multiple transthoracic echocardiograms over that period.

        Finally, I believe PUFAs cause higher values of Lp(a) and saturated fat can lower these values. I’m in the process of setting up a test of this to verify, though whether I can afford the costs of the multiple blood tests will be a factor as to whether I can do the actual test.

  4. Lp(a) is due because the human body cannot produce vitamin C. As a result Lp(a) is the patchwork necessary when micro tears occur within the arterial wall (i.e. endothelium aka glycocalyx). This is well documented by the research done by Drs. Rath & Pauling.

    Dr. Rath concluded that sufficient amounts of L-Pro and L-Lys would in effect remove the Lp(a) residue. This in conjunction with mega-dosing Vit. C would far exceed niacin therapy or PCSK9 both of which only reduce 20-30 % Lp(a). B3 over time raises FBS, PCSK9s have been reported to cause ‘neurocognitive effects’ (attention deficit and confusion) and Antisense Oligonucleotides have an FDA Warning label for hepato-toxcicity, elevated serum transaminase, and hepatic steatosis

    Reply

  5. Thanks Doc! Particularly relevant to both myself and family. My father recently had a TAVI due to AO. A background in endurance sports (Int. level) and still riding at 82yrs with very clear coronary arteries. We have near identical cholesterol profiles and I’ve been logging miles most of my life. A recent echo showed no stenosis but it’s on my radar and won’t be unexpected. Keep writing!

    Reply

  6. Speaking of entering the arterial wall, a research paper from the Salk Institute a couple of months ago seems to show that the spike protein used by Covid to enter cells and released/created? by mRNA vaccines may cause vascular damage.

    =========
    Salk researchers and collaborators show how the protein damages cells, confirming COVID-19 as a primarily vascular disease
    April 30, 2021
    https://www.salk.edu/news-release/the-novel-coronavirus-spike-protein-plays-additional-key-role-in-illness/
    ===========

    Do you have any thoughts on this aspect of Covid & related mRNA vaccines?

    Reply

  7. I just received my full lipid panel after my dad passed away from atherosclerosis. My total cholesterol is 214, HDL 62, LDL-C 135, non-HDL 152, LDL-P 1,474, Apolipoprotein B 105, Lipoprotein 206, trigylcerides 71. I’m only 33, do not have high blood pressure or diabetes, but am slightly overweight. I’m not sure if I should be concerned or not, but given the circumstances with my dad recently passing, I’m scared. Should I be on medication or is this something I can correct with lifestyle modifications?

    Reply

    • Yes I would be concerned. While you are still young you can control your high cholesterol levels by eating healthy and exercising regularly. However if you are not able to significantly reduce these mentioned cholesterol levels in another 6 months then you should be on low dose statins ( prescribed cholesterol lowering drugs)

      Reply

  8. So if you have a score of 9 nmol / L (lab ref value <75) for Lp(a) and HDL of 58, Triglycerides of 62, Total of 186 and LDL of 114 and hs-CRP of .45, yet have a CAC score of 385 in the LAD and 0 in two other arteries and 50 in the remaining one. Particle number 1164 (down from 1450 7 years prior), small LDL-P 202 nmol/L (lab ref 20.5). 70 years old with type 1.5 diabetes (20+years)rheumatoid arthritis of 20+ years (in remission with Enbrel for past 8 years). HBA1c of 5.8.

    Eat 20% carbs, 25% protein, 55% fat. Walk 5 miles/day at 4mph pace – semi-hilly terrain. Heart rate gets up to 135 at peak of walk. No difficulties with breathing or chest pain.

    What do you make of the CAC score and what to do about it based on my numbers and info above? Docs all want me on statins. Have declined this option due to having too many friends with serious issues from them. I am trying to eat a low inflammatory diet with high doses of fish oil, 1-2 grams of Kyolic Aged Garlic Extract, CoQ10 (200mg/day), multi-Vit, Quercetin, Circumin, folate,Vit D 5000IU,400-600mg of chelated Magnesium, Collagen powder. Thinking about taking d-ribose and l-carnitine per Dr Stephan Sinatra theory of providing additional energy to the heart.

    Thanks for any thoughts you might have!
    Mark

    Reply

  9. 56 year old Male, CAC 12.9, 12 of that in Right coronary. TC 209, LDL 138, Trig 122, but I have high bp, especially in AM upon waking, varies wildly, e.g. 160/101 ten minutes after waking, down to 127/78 one hour later. Trying to fix diet, not easy.

    Reply

  11. I have a calcium score of about 3500
    Had a double bypass January due to severely calcified blocked coronary veins
    And have lp(a) level of 839 mg/l

    What is my prognosis and can I do something to improve this besides healthy food and daily sport/ training what I am already doing

    I use ezetimibe because cannot use statins due to muscle/ boneproblems

    Reply

  12. Axel, I am writing a paper on Lp(a) and would like to use your diagram of the LDL and Lp(a) particles if that is possible.

    Thanks for a good article!

    Reply

  13. Hi, could I use you LDL/Lp(a) image for a presentation? In this case, a picture is worth a thousand words, and I feel like your image is doing a particularly good job.
    Thank you

    Reply

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