“Little Napoleon Complex”: Lp (a)
A CardioAdvocate Phenotype
Case Presentation: Bob Harper's Heart Attack
The story of Bob Harper's heart attack on February 12, 2017 brought to light two very important aspects of ASCVD risk:
- Optimizing modifiable risk factors alone does not eliminate the risk of heart attack. You can't "run" away from your genetics.
- Lipoprotein (a) or Lp(a) - pronounced "Lp little a" - warrants screening and treatment.
Many know Bob Harper as the celebrity personal trainer from NBC's reality TV show The Biggest Loser. As a fitness expert, Bob Harper was the epitome of health - eating healthy and exercising regularly. But at age 51 Bob suffered a massive heart attack in the gym during a workout. Fortunately there was a doctor in the room and he received prompt CPR and defibrillation from an available AED.
Bob reportedly had normal cholesterol but his Lp(a) was "perilously high" (The Harmful Blood Particle You've Never Heard Of — Cleveland HeartLab). About 90% of Lp(a) particle numbers are determined by genetics. Bob had a family history of heart disease - his mother died of a heart attack. But he's not alone - about 1 in 5 of us have elevated Lp(a) levels (> 50 mg/dL or > 125 nmol/L), making it the most common familial lipid abnormality causal to atherosclerosis.
Flying Under the Radar
If you've never been tested and you're asking "What is Lp(a)?" - you're not alone. Fewer than 2% of those who have ever had a lipid panel have also been tested for Lp(a), and shockingly, < 3% of those with established heart disease (Lipoprotein(a) Testing Trends in a Large Academic Health System in the United States).
Routine testing of Lp(a) in those with established ASCVD can better identify those with heightened risk for recurrent events and assist in management (Elevated lipoprotein(a) increases risk of subsequent major adverse cardiovascular events (MACE) and coronary revascularisation in incident ASCVD patients: A cohort study from the UK Biobank).
The high prevalence of this risk factor (1.4 billion globally), coupled with the mind-blowing lack of awareness, makes this phenotype particularly dangerous. Lipoprotein(a) is causal to both atherosclerosis and calcific aortic stenosis.
Lp(a) is a Continuous Causal Risk Factor for ASCVD Events
As its concentration increases linearly, so does the risk for ASCVD events. When added to polygenic risk scores (PRS), those with the highest PRS and high Lp(a) (> 125 nmol/L) had a 5 times higher risk of ASCVD event compared to low PRS and low Lp(a) (Contribution of Lipoprotein(a) to Polygenic Risk Prediction of Coronary Artery Disease: A Prospective UK Biobank Analysis).
Lp(a) is Atherogenic
Lp(a) is a member of the "atherogenic lipoprotein" species. It's an LDL-like particle with an apolipoprotein(a) attached by a disulfide bond to ApoB. It not only delivers cholesterol, but also oxidized phospholipids on its membrane, into the artery wall.
Lp(a) is Prothrombotic
Lp(a) may promote clotting more readily. Those who rupture a plaque may be more prone to catastrophic clotting events. Lp(a) has homologous regions to plasminogen - having too much Lp(a) may prevent plasminogen from breaking down clots when it should.
Lp(a) is Causal to Calcific Aortic Stenosis
Lp(a) increases expression of vascular and valvular calcification genes. Those above the 80th percentile (50 mg/dL) have a 3x higher risk of aortic stenosis. Aortic stenosis is predicted to increase by > 300% by 2050 (Lipoprotein(a) in atherosclerotic cardiovascular disease and aortic stenosis: a European Atherosclerosis Society consensus statement).
Lp(a) Risk is Familial and Common
Lp(a) particle number is highly inheritable, with the apo(a) gene accounting for > 90% of variability. Since high Lp(a) affects 1 in 5 of us, it represents the most common genetic lipid abnormality causal to atherosclerosis and aortic stenosis.
Lp(a) Screening is Recommended
The European Society of Cardiology and the Canadian Cardiovascular Society (2021 Guidelines) recommend screening the entire population for elevated Lp(a) at least once, to rule out very high levels which can dramatically increase risk equivalent to HeFH (25x risk). See our phenotype "Hiding in Plain Sight - Familial Hypercholesterolemia."
In an effort to increase awareness, Bob partnered with AstraZeneca for Survivors Have Heart with his essay Moving Forward as a Heart Attack Survivor. If your Lp(a) is elevated, consider cascade screening for family members. March 24th is National Lp(a) Day.
CardioAdvocate Checklist
Patient Questions - Know Your Status
If Lp(a) is Elevated - Action Items
Questions to Ask Your Clinician
- "Has my Lp(a) ever been checked?"
- "Given my family history of heart disease, should I have my Lp(a) tested?"
- "If my Lp(a) is elevated, should my children and siblings be tested too?"
- "Are there clinical trials for new Lp(a)-lowering drugs I might qualify for?"
- "How aggressively should we treat my other risk factors given my elevated Lp(a)?"
Deep Dive: Understanding Lp(a)
What is Lp(a)?
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 "Kringle repeats" - molecular structures that look like a Kringle Danish pastry. Within the domain KIV² there may be just a few or multiple copies, determining particle size. There's an inverse relationship: fewer repeats = more particles. Levels can vary up to 1000-fold between individuals. The Apo(a) gene accounts for 90% of variability.
Atherogenic Mechanism
While Lp(a) is an LDL-like particle capable of trafficking cholesterol esters and infiltrating the endothelial wall, the majority of its contribution to atherosclerosis comes from oxidized phospholipids on its polar membrane. Pound for pound, oxidized phospholipids contribute more to inflammation through cell signaling rather than plaque accumulation.
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 than LDL on a per-particle basis.
As for its ApoB contribution, there is a 1:1 relationship of apoB to Lp(a). If Lp(a) is 125 nmol/L, this means the apoB contribution from Lp(a) is also 125 nmol/L. Dividing by conversion factor 19.49 gives an apoB of 6.4 mg/dL attributable to Lp(a). But even with low LDL-C, very high Lp(a) remains a risk factor.
Thrombogenic Mechanism
Apolipoprotein(a) has regions closely related (homologous) to plasminogen. Plasminogen breaks down clot (thrombolysis). Lp(a) may compete for plasminogen binding sites - in those with high Lp(a), this may promote clot formation when it shouldn't occur.
Plaque rupture is the most common mechanism for heart attack. When that endothelial "cap" breaks down from inflammation, it releases Tissue Factor and other thrombogenic compounds, activating thrombin, platelets, and the coagulation cascade. The fear for those with very high Lp(a) is that when they rupture a plaque, they do it big time - that snowball builds fast while plasminogen is being "stiff armed" by Lp(a).
Therefore, ASCVD events in patients with high Lp(a) are more likely to be of a "thrombotic" variety - meaning heart attack or stroke - and tend to be "premature," or earlier in life.
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 from elevated Lp(a) is to target other modifiable risk factors more aggressively than we might otherwise.
Therapies NOT Recommended for Lp(a) Lowering
Niacin
Does lower Lp(a), but has fallen out of favor after two major trials failed to show clinical benefit:
- The NHLBI-funded AIM-HIGH trial (2011) showed no clinical benefit beyond statins despite improvements in HDL-C (not surprisingly as we discuss elsewhere in What's Your ApoB?) and triglycerides.
- The HPS2-THRIVE trial (2014) showed no benefit but significant side effects including diabetes, GI upset, musculoskeletal problems, infection, and bleeding.
Estrogen
Modestly lowers Lp(a), but the potential side effects of hormone replacement therapy do not justify its use for this indication.
PCSK9 Inhibitors and Lp(a)
PCSK9 inhibitors do lower Lp(a) (~25-30%), but are not approved for Lp(a) lowering. There were some favorable subgroup analysis data from the FOURIER (Lipoprotein(a), PCSK9 Inhibition, and Cardiovascular Risk) 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 vs. threshold reductions needed to achieve benefit.
2026: The Year of Lp(a) — Therapies on the Horizon
We are on the verge of a new era in Lp(a) treatment. Five drugs targeting Lp(a) are advancing toward phase 3 readouts, and results from the first cardiovascular outcomes trials (CVOTs) are expected in 2026. These trials will finally answer the critical question: Does lowering Lp(a) reduce cardiovascular events?
According to the ACC Feature on Lp(a), the Cleveland Clinic Journal of Medicine, and coverage from the National Lipid Association 2025 Meeting, here's where we stand:
| Drug | Company | Type | Lp(a) Reduction | Route | Trial (n) | Expected Results |
|---|---|---|---|---|---|---|
| Pelacarsen | Novartis / Ionis | ASO | ~80% | SQ monthly | Lp(a)HORIZON (8,323) | 1H 2026 ★ |
| Olpasiran | Amgen | siRNA | ~94–95% | SQ q12 weeks | OCEAN(a)-Outcomes (7,200) | Late 2026 ★ |
| Lepodisiran | Eli Lilly | siRNA | ~94% | SQ q24–48 weeks | ACCLAIM-Lp(a) (16,700) | 2027–2028 |
| Zerlasiran | Silence Therapeutics | siRNA | >90% | SQ q16–24 weeks | ALPACAR-360 (Ph2) | Phase 3 pending partner |
| Muvalaplin | Eli Lilly | Small molecule | ~63–65% | Oral daily | MOVE-Lp(a) (10,450) | 2031 |
Color key: Blue = Antisense Oligonucleotide (ASO) | Green = Small Interfering RNA (siRNA) | Gold = Oral Small Molecule | ★ = CVOT results expected 2026
ASO = Antisense Oligonucleotide | siRNA = Small Interfering RNA | SQ = Subcutaneous
Antisense Oligonucleotides (ASOs)
Pelacarsen (Novartis/Ionis)
An ASO that inhibits apolipoprotein(a) production by targeting its messenger RNA. Phase 2 demonstrated ~80% reduction in Lp(a) with monthly subcutaneous injections. The Lp(a)HORIZON trial is a phase 3 CVOT enrolling 8,323 patients with established CVD and Lp(a) ≥70 mg/dL. Results expected 1H 2026 — this will be the first CVOT to report on Lp(a)-lowering therapy.
Small Interfering RNA (siRNA)
Olpasiran (Amgen)
A siRNA that blocks Lp(a) production by inducing degradation of apolipoprotein(a) mRNA. Phase 2 results from OCEAN(a)-DOSE showed ~94-95% reduction in Lp(a) at 36 weeks with quarterly dosing. The OCEAN(a)-Outcomes trial (TIMI 75) enrolls 7,200 patients. Results expected late 2026.
Lepodisiran (Eli Lilly)
A siRNA producing durable reductions with infrequent dosing. Phase 2 showed ~94% reduction in Lp(a) sustained through day 360 after a single dose (Cleveland Clinic Newsroom). The ACCLAIM-Lp(a) trial enrolls up to 16,700 patients — the largest of all ongoing Lp(a) studies. Results expected 2027-2028.
Zerlasiran (Silence Therapeutics)
A siRNA that completed the phase 2 ALPACAR-360 study with >90% Lp(a) reduction. The company has received FDA feedback for phase 3 but initiation depends on finding a development partner.
Oral Small Molecule
Muvalaplin (Eli Lilly)
An oral small molecule that inhibits Lp(a) formation by blocking the initial interaction between apo(a) and apoB. Phase 2 (KRAKEN trial) showed ~63-65% reduction with once-daily oral dosing. The MOVE-Lp(a) trial enrolls 10,450 patients. While less dramatic reduction than siRNA agents, it offers the significant advantage of oral administration. Results expected 2031.
The Big Question
While these Lp(a) reductions are striking, no published outcome trial has definitively shown that Lp(a) lowering reduces major cardiovascular events. Mendelian Randomization studies suggest substantial Lp(a) lowering (>50-100 mg/dL) may be required for meaningful risk reduction. The ongoing CVOTs will answer whether 65-95% Lp(a) reduction translates into fewer heart attacks and strokes.
If positive, 2026 could mark a paradigm shift in cardiovascular prevention.
The Bottom Line
Lp(a) may be little, but it punches well above its weight class — the original "Little Napoleon Complex."
About 1 in 5 of us have elevated Lp(a), making it the most common genetic lipid disorder causal to atherosclerosis. Yet fewer than 2% of those with lipid panels have ever been tested. This has to change.
Until now, all we could do was optimize other risk factors. But 2026 may change everything. The first CVOTs of direct Lp(a)-lowering therapies will report results, potentially ushering in a new era where this "untreatable" risk factor becomes treatable.
If you have heart disease, a family history of premature heart disease, or want to understand your complete cardiovascular risk profile — ask for your Lp(a) to be checked. If it's elevated, inform your family members so they can be tested too.
Don't let your Little Napoleon fly under the radar.
