Apolipoprotein B and Heart Disease: Peter Attia's View

Table of Contents

1. Where His Heart-Disease Argument Appears
2. Heart Disease as a Silent Killer
3. The Most Preventable of the Four Horsemen
4. Apolipoprotein B: Counting the Particles
5. Apolipoprotein B Compared With Low-Density Lipoprotein Cholesterol
6. How the Particles Get Into the Artery Wall
7. Genetics and a Lifetime of Exposure
8. Lipid-Lowering Drugs in His View and in the Trials
9. Lipoprotein(a): The Inherited Particle
10. Testing, Imaging and the Brain in His Framework
11. Key Research Papers
12. Connections

1. Where His Heart-Disease Argument Appears

Heart disease has its own chapter in Outlive. The book’s published chapter list gives it the title “The ticker: confronting and preventing heart disease, the deadliest killer on the planet”. It sits among the chapters on the four horsemen, between the chapter on metabolic disease (“The crisis of abundance”) and the chapter on cancer (“The runaway cell”).

His clearest first-hand statement of the argument on his own website is a weekly article published on 17 August 2024 under the title “Coronary atherosclerosis is a silent killer, but we have tools to stop it”. It is signed by Kathryn Birkenbach, Tom Dayspring and Peter Attia. Dayspring is a physician who has appeared on his podcast to discuss cholesterol and lipoproteins. The article discusses a then-new observational study of coronary plaque in adults with no symptoms, and the quotations in the sections below come from it unless another source is named.

His website also keeps a standing topic page on heart disease, which gathers his earlier articles and podcast episodes on atherosclerosis, coronary disease, cholesterol and apolipoprotein B. Those episodes are not quoted here, because only their titles and summaries, not their text, were available.

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2. Heart Disease as a Silent Killer

Attia’s starting point is that atherosclerosis — the slow build-up of fatty plaque inside the walls of arteries — gives little warning. On his heart-disease topic page he writes that one of the most frightening things about it is that it is “often a silent killer, with few to no outward symptoms”. He recalls a medical-school professor who liked to point out that the most common “presentation” of the disease is a sudden, fatal heart attack: the patient is known to have had heart disease only because he has just died of it.

The 2024 article opens with the same theme. It notes that heart disease again led the causes of death in the United States in the preliminary national mortality report for 2023, a position it has held for the past two decades. The study the article discusses looked at adults aged 40 to 65 from a Miami heart study who had no symptoms, no high blood pressure, no diabetes, no tobacco use and no cholesterol-lowering medicine. Scans of their coronary arteries nonetheless found plaque in a large share of them, including in a small group the study classed as being at the very lowest risk.

From this the article draws its main point: that millions of people with the disease are probably unaware of it, because it develops over decades and because young or otherwise healthy people, and their doctors, often do not look for it. In Attia’s reading, the problem is not a lack of tools but a lack of looking.

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3. The Most Preventable of the Four Horsemen

Attia groups most deaths in non-smokers over 50 into four categories — atherosclerotic disease, cancer, neurodegenerative disease and metabolic disease — which he calls the four horsemen (see The Four Horsemen: Peter Attia on Chronic Disease). Of the four, he treats heart disease as the one where the most can be done.

The 2024 article states that coronary atherosclerosis, which is responsible for the majority of deaths from cardiovascular disease, “is easily the most preventable of all the ‘four horsemen of chronic disease’”. The reason he gives is that, in his view, the cause is known and can be measured: the disease, the article says, “is caused by [apolipoprotein B]-containing lipoproteins”.

The article ends on the same note. After arguing that testing and treatment could prevent most deaths from the disease, it closes: “One horseman down, three to go.” The line sums up how he ranks the four: heart disease as a problem he regards as largely solvable, the others as harder.

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4. Apolipoprotein B: Counting the Particles

Cholesterol and fats do not dissolve in blood, so they travel inside small particles called lipoproteins. The best known is low-density lipoprotein (LDL), often called “bad cholesterol”; others include very-low-density lipoprotein, the remnants left after these particles give up their fat, and lipoprotein(a). Each of these particles carries one molecule of a structural protein, apolipoprotein B, wrapped around it. Measuring apolipoprotein B in the blood is therefore a way of counting how many of these particles are present.

Attia’s argument rests on that fact. The 2024 article says that “atherogenesis depends on the number of [apolipoprotein B]-containing lipoproteins” — that is, the start of plaque depends on how many particles there are — “rather than on their cholesterol content”. The ordinary cholesterol test measures how much cholesterol the low-density lipoprotein particles carry in total; apolipoprotein B counts the particles themselves. In his view, the count is the closer measure of the cause.

A 2019 narrative review in JAMA Cardiology by Allan Sniderman and colleagues sets out the same reasoning in detail. Its abstract states that cholesterol can only enter the artery wall inside apolipoprotein B particles; that the number of particles entering the wall is set mainly by the number in the bloodstream; and that, while smaller cholesterol-poor particles tend to be trapped more readily and larger cholesterol-rich ones carry more cholesterol each, the net result is that, apart from two exceptions (abnormal remnant particles in a rare inherited disorder, and lipoprotein(a)), “all [apolipoprotein B] particles are equally atherogenic”. The review concludes that apolipoprotein B “unifies, amplifies, and simplifies” the information from the usual lipid tests.

The site’s laboratory page Apolipoprotein B (ApoB) describes the test itself, and the animation Cholesterol, Low-Density Lipoprotein (LDL) and the Artery Wall shows the particles in motion.

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5. Apolipoprotein B Compared With Low-Density Lipoprotein Cholesterol

The 2024 article uses the Miami study to compare the two measures. In that study, it reports, the share of people with coronary plaque rose with each lipid measure, but more steeply with apolipoprotein B: “each 10 mg/dL increase in [low-density lipoprotein cholesterol] was associated with a 13% increase in risk”, while “each 10 mg/dL increase in [apolipoprotein B] was associated with a 20% increase in risk”. The authors call the stronger link with apolipoprotein B “in line with expectations”, since in their view plaque depends on the number of particles.

The article is careful about what such a study can show. It describes the Miami work as observational and based on a single snapshot in time, and says that on its own it “tells us nothing about any causal relationship” between apolipoprotein B and cardiovascular disease. The authors place it instead alongside what they describe as a large and consistent body of earlier evidence.

Several of the papers in that body of evidence compare the measures directly:

• Sniderman and colleagues, 2011. A meta-analysis of 12 independent reports covering 233,455 people and 22,950 fatal or non-fatal heart and vessel events. Whether analysed alone or head to head, apolipoprotein B was the strongest marker of risk (relative risk ratio 1.43), low-density lipoprotein cholesterol the weakest (1.25), and non-high-density lipoprotein cholesterol in between (1.34). The authors estimated that, over ten years, treating the top 30% of United States adults by apolipoprotein B rather than by the other two measures would prevent several hundred thousand more events.
• Marston and colleagues, 2022. An analysis of 389,529 people in a large British population database who were not taking cholesterol-lowering medicine, and 40,430 patients with established atherosclerosis from two drug trials. When apolipoprotein B, non-high-density lipoprotein cholesterol and triglycerides were assessed together, only apolipoprotein B remained linked to heart attack (hazard ratio 1.27 per standard deviation). The authors wrote that heart-attack risk “was best captured by the number of [apolipoprotein B]-containing lipoproteins, independent from lipid content”.

The site’s page Cholesterol Management covers the standard lipid tests these papers compare.

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6. How the Particles Get Into the Artery Wall

The 2024 article describes the process in one line: the particles carrying apolipoprotein B “penetrate artery walls and initiate atherogenesis”. This is the idea that plaque begins when particles from the blood slip under the thin inner lining of an artery and become stuck there.

A 2007 review in Circulation by Ira Tabas, Kevin Jon Williams and Jan Borén set out this “response to retention” model. Its abstract states that “the key initiating process in atherogenesis is the subendothelial retention of apolipoprotein B-containing lipoproteins”, and that the body’s reaction to these trapped particles — a long-lasting inflammatory response led by white blood cells — drives the growth of the plaque. The review notes that populations who keep lifelong low levels of these particles have roughly a 90% lower risk of coronary artery disease.

Two consensus statements from the European Atherosclerosis Society take the same position on cause. The first, published in 2017 and led by Brian Ference, weighed genetic studies, long-term cohort studies, Mendelian randomisation studies and randomised drug trials covering more than 2 million participants and over 150,000 cardiovascular events. It found a “remarkably consistent” dose-dependent link between the amount of low-density lipoprotein cholesterol the arteries are exposed to and the risk of atherosclerotic disease, a link that appeared to grow with the length of exposure, and concluded that the evidence “unequivocally establishes that [low-density lipoprotein] causes” atherosclerotic cardiovascular disease. The second statement, published in 2020 and led by Jan Borén, addressed the mechanism — how the particles enter and are held in the artery wall — along with the genetic and treatment evidence.

The site’s page Atherosclerosis describes the disease itself, and Goldstein & Brown tells the story of the receptor that clears these particles from the blood.

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7. Genetics and a Lifetime of Exposure

A theme that runs through Attia’s writing is starting early: in his Medicine 3.0 framework he calls for prevention decades before disease appears (see Medicine 3.0). The 2024 article applies this to the heart, describing atherosclerosis as something that “develops over decades of exposure” to high levels of these particles.

Studies of people born with gene variants that lower their cholesterol from birth bear on this question. Because such variants are handed out at conception largely by chance, researchers use them as a natural experiment, a method called Mendelian randomisation.

• Cohen and colleagues, 2006. In a 15-year study of a large United States community, 2.6% of the 3,363 Black participants carried variants that switch off the gene for proprotein convertase subtilisin/kexin type 9 (PCSK9), a protein that removes the receptors clearing low-density lipoprotein from the blood. These carriers had 28% lower low-density lipoprotein cholesterol and an 88% lower risk of coronary heart disease. Among 9,524 white participants, 3.2% carried a milder variant linked to 15% lower cholesterol and 47% lower risk.
• Ference and colleagues, 2012. A combined analysis of nine gene variants in six genes, covering 312,321 people, found that lifelong exposure to lower low-density lipoprotein cholesterol was linked to a 54.5% lower risk of coronary heart disease for each 1 mmol/L (38.7 mg/dL) lower level — about three times the reduction seen per unit when a statin is started later in life.
• Ference and colleagues, 2019. Compared gene variants that lower triglycerides with variants that lower low-density lipoprotein cholesterol, in 654,783 people including 91,129 with coronary heart disease. Both kinds of variant were linked to a similar lower risk for each 10 mg/dL lower apolipoprotein B, and once apolipoprotein B was taken into account, the links with triglycerides and with low-density lipoprotein cholesterol disappeared. The authors concluded that the benefit of lowering either “may be proportional to the absolute change in [apolipoprotein B]”.
• Richardson and colleagues, 2020. A Mendelian randomisation analysis using data from a large British population database and a large international coronary-disease consortium. Taken one at a time, low-density lipoprotein cholesterol, triglycerides and apolipoprotein B each pointed to higher risk; analysed together, only apolipoprotein B kept a robust effect. The authors wrote that apolipoprotein B is “the predominant trait” behind the link between blood lipids and coronary heart disease, while noting that the different lipid measures are closely correlated, which makes it hard to assign cause to any single one.

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8. Lipid-Lowering Drugs in His View and in the Trials

Attia’s view of cholesterol-lowering medicines is strongly favourable. The 2024 article says that therapies which lower circulating low-density lipoprotein — it names statins and the drugs that block proprotein convertase subtilisin/kexin type 9 — “have the power to virtually stop atherosclerosis in its tracks”. It argues that being proactive about lipid tests and imaging, and following up with treatment, could make the difference between life and death for an individual, and that “On a population scale, these actions have the power to put an end to mortality from coronary atherosclerosis.” These are his and his co-authors’ views; this page reports them and does not describe any treatment plan or dose.

His website also describes, in general terms, how his practice approaches any medicine or supplement: it asks what the objective is, whether there is a blood marker to track the effect, and whether the risk outweighs the reward.

Two large bodies of trial evidence bear on these drugs:

• The Cholesterol Treatment Trialists’ Collaboration, 2010. A meta-analysis of individual patient data from 26 randomised statin trials with about 170,000 participants. Each 1.0 mmol/L reduction in low-density lipoprotein cholesterol cut the yearly rate of major vascular events (heart attack, artery-opening procedures and stroke caused by a blocked artery) by just over a fifth, with no threshold found in the range studied, including in people whose starting levels were already below 2 mmol/L. Deaths from all causes fell by 10% per 1.0 mmol/L, mainly through fewer deaths from coronary heart disease. The authors found no significant effect on cancer deaths or on new cancers.
• The FOURIER trial, 2017. A randomised, placebo-controlled trial of evolocumab, an injected antibody against proprotein convertase subtilisin/kexin type 9, in 27,564 people with established atherosclerotic disease who were already taking a statin. Low-density lipoprotein cholesterol fell by 59%, to a median of 30 mg/dL, and over a median 2.2 years the combined rate of cardiovascular death, heart attack, stroke, hospital admission for unstable angina or artery-opening procedures fell from 11.3% to 9.8% (hazard ratio 0.85). The trial reported no significant difference in adverse events, including new-onset diabetes and effects on thinking, except injection-site reactions, which were more common with the drug (2.1% versus 1.6%). The trial was funded by the drug’s manufacturer.

The site’s page Coronary Artery Disease (CAD) covers the disease these trials target.

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9. Lipoprotein(a): The Inherited Particle

Lipoprotein(a) is a low-density-lipoprotein-like particle with an extra protein attached. Its level in the blood is set mainly by inheritance and changes little over a lifetime. Attia’s first-hand statements on it were not available to us. Published summaries of his podcast episodes — including an “Ask Me Anything” episode and an episode with the Canadian researcher Benoît Arsenault — describe him discussing lipoprotein(a) as a separate, inherited risk factor for heart disease. That description comes from those third-party summaries, not from his own text.

Two papers describe where the research stood:

• Nordestgaard and colleagues, 2010. A European Atherosclerosis Society consensus panel concluded that the “robust and specific” link between high lipoprotein(a) and heart and vessel disease, together with genetic findings, indicates that high lipoprotein(a), like high low-density lipoprotein cholesterol, is causally related to premature cardiovascular disease, with no threshold and independent of other cholesterol levels. The panel advised measuring it once in people at intermediate or high risk, and proposed a desirable level below about 50 mg/dL (the 80th percentile).
• Tsimikas, 2017. A review in the Journal of the American College of Cardiology describing lipoprotein(a) as an independent, genetic and likely causal risk factor for cardiovascular disease and for calcific narrowing of the aortic valve. It notes that statins tend to raise lipoprotein(a) levels, that the drugs blocking proprotein convertase subtilisin/kexin type 9 lowered it by 20% to 30%, and that experimental RNA-targeted therapies lowered it by more than 80% — which, the review states, would allow the “lipoprotein(a) hypothesis” to be tested in clinical trials.

The site’s laboratory page Lipoprotein(a) describes the test.

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10. Testing, Imaging and the Brain in His Framework

In Attia’s framework the blood test and the scan work together. The 2024 article describes two kinds of heart imaging used in the Miami study: the coronary artery calcium (CAC) scan, a quick computed tomography scan that detects calcium in the walls of the heart’s arteries, and coronary computed tomography angiography, a contrast scan that can also show soft plaque that has not yet calcified. The article reports that in the low-risk Miami group more people had plaque on the angiography scan than had a calcium score above zero.

The article criticises the habit of not looking: it says that for younger or otherwise healthy people, both patients and doctors often overlook the possibility of coronary artery disease and fail to check for it with a coronary artery calcium scan or coronary computed tomography angiography, even when low-density lipoprotein cholesterol is known to be high. It presents apparent good health as no guarantee that the disease is absent. The site’s laboratory page Coronary Calcium Score describes the scan.

Attia also links the heart to the brain. On his website’s page on neurodegenerative disease he writes that, apart from genetics, the next most common risk factor his practice sees for dementia is vascular disease, and that the factors that raise the risk of atherosclerosis — he names high blood pressure, smoking and elevated apolipoprotein B — also raise the risk of dementia. He sums this up with the saying that what is good for the heart is good for the brain. This ties his heart-disease chapter to his chapter on Alzheimer’s disease (see The Four Horsemen).

Finally, his lipid argument sits beside the rest of his programme rather than replacing it. In the same framework he lists exercise, sleep, nutrition, medicines and supplements, and emotional health as his five tactics against all four horsemen; those are covered on Exercise, VO2 Max and the Centenarian Decathlon and Nutrition and Sleep in Peter Attia’s Outlive.

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Key Research Papers

1. Ference BA, Ginsberg HN, Graham I, Ray KK, Packard CJ, Bruckert E, et al. Low-density lipoproteins cause atherosclerotic cardiovascular disease. 1. Evidence from genetic, epidemiologic, and clinical studies. A consensus statement from the European Atherosclerosis Society Consensus Panel. Eur Heart J. 2017;38(32):2459-2472. — PubMed PMID: 28444290
2. Borén J, Chapman MJ, Krauss RM, Packard CJ, Bentzon JF, Binder CJ, et al. Low-density lipoproteins cause atherosclerotic cardiovascular disease: pathophysiological, genetic, and therapeutic insights: a consensus statement from the European Atherosclerosis Society Consensus Panel. Eur Heart J. 2020;41(24):2313-2330. — PubMed PMID: 32052833
3. Tabas I, Williams KJ, Borén J. Subendothelial lipoprotein retention as the initiating process in atherosclerosis: update and therapeutic implications. Circulation. 2007;116(16):1832-44. — PubMed PMID: 17938300
4. Sniderman AD, Thanassoulis G, Glavinovic T, Navar AM, Pencina M, Catapano A, et al. Apolipoprotein B Particles and Cardiovascular Disease: A Narrative Review. JAMA Cardiol. 2019;4(12):1287-1295. — PubMed PMID: 31642874
5. Sniderman AD, Williams K, Contois JH, Monroe HM, McQueen MJ, de Graaf J, et al. A meta-analysis of low-density lipoprotein cholesterol, non-high-density lipoprotein cholesterol, and apolipoprotein B as markers of cardiovascular risk. Circ Cardiovasc Qual Outcomes. 2011;4(3):337-45. — PubMed PMID: 21487090
6. Marston NA, Giugliano RP, Melloni GEM, Park JG, Morrill V, Blazing MA, et al. Association of Apolipoprotein B-Containing Lipoproteins and Risk of Myocardial Infarction in Individuals With and Without Atherosclerosis: Distinguishing Between Particle Concentration, Type, and Content. JAMA Cardiol. 2022;7(3):250-256. — PubMed PMID: 34773460
7. Richardson TG, Sanderson E, Palmer TM, Ala-Korpela M, Ference BA, Davey Smith G, et al. Evaluating the relationship between circulating lipoprotein lipids and apolipoproteins with risk of coronary heart disease: A multivariable Mendelian randomisation analysis. PLoS Med. 2020;17(3):e1003062. — PubMed PMID: 32203549
8. Ference BA, Kastelein JJP, Ray KK, Ginsberg HN, Chapman MJ, Packard CJ, et al. Association of Triglyceride-Lowering LPL Variants and LDL-C-Lowering LDLR Variants With Risk of Coronary Heart Disease. JAMA. 2019;321(4):364-373. — PubMed PMID: 30694319
9. Ference BA, Yoo W, Alesh I, Mahajan N, Mirowska KK, Mewada A, et al. Effect of long-term exposure to lower low-density lipoprotein cholesterol beginning early in life on the risk of coronary heart disease: a Mendelian randomization analysis. J Am Coll Cardiol. 2012;60(25):2631-9. — PubMed PMID: 23083789
10. Cohen JC, Boerwinkle E, Mosley TH Jr, Hobbs HH. Sequence variations in PCSK9, low LDL, and protection against coronary heart disease. N Engl J Med. 2006;354(12):1264-72. — PubMed PMID: 16554528
11. Cholesterol Treatment Trialists’ (CTT) Collaboration, Baigent C, Blackwell L, Emberson J, Holland LE, Reith C, et al. Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised trials. Lancet. 2010;376(9753):1670-81. — PubMed PMID: 21067804
12. Sabatine MS, Giugliano RP, Keech AC, Honarpour N, Wiviott SD, Murphy SA, et al. Evolocumab and Clinical Outcomes in Patients with Cardiovascular Disease. N Engl J Med. 2017;376(18):1713-1722. — PubMed PMID: 28304224
13. Nordestgaard BG, Chapman MJ, Ray K, Borén J, Andreotti F, Watts GF, et al. Lipoprotein(a) as a cardiovascular risk factor: current status. Eur Heart J. 2010;31(23):2844-53. — PubMed PMID: 20965889
14. Tsimikas S. A Test in Context: Lipoprotein(a): Diagnosis, Prognosis, Controversies, and Emerging Therapies. J Am Coll Cardiol. 2017;69(6):692-711. — PubMed PMID: 28183512

PubMed Topic Searches

1. Apolipoprotein B and cardiovascular risk
2. Apolipoprotein B compared with low-density lipoprotein cholesterol
3. Mendelian randomisation of low-density lipoprotein and coronary heart disease
4. Lipoprotein(a) and cardiovascular disease
5. Coronary artery calcium in people without symptoms

Further Reading

• Birkenbach K, Dayspring T, Attia P — “Coronary atherosclerosis is a silent killer, but we have tools to stop it”, 17 August 2024
• Peter Attia MD — “Risks” (the four horsemen)
• Peter Attia MD — Outlive book page
• Wellcome Collection catalogue record of Outlive (British edition, with chapter list)

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Connections

• Dr. Peter Attia: Outlive and the Science of Longevity
• Peter Attia: Life and Career
• Medicine 3.0: Peter Attia’s Framework for Longevity
• The Four Horsemen: Peter Attia on Chronic Disease
• Exercise, VO2 Max and the Centenarian Decathlon
• Nutrition and Sleep in Peter Attia’s Outlive
• Contemporary Practitioners
• Apolipoprotein B Test
• Lipoprotein(a) Test
• Coronary Calcium Score
• Atherosclerosis
• Goldstein & Brown: The Low-Density Lipoprotein Receptor