Disclaimer: I’m not a doctor or specialized in this topic in any way.

Summary: Atherosclerosis is the number one cause of death and disability in the developed world. A large part might be preventable with lifestyle changes, medication and supplements. I am trying to figure out if I should start doing that and I am looking for feedback.

Note: Atherosclerosis is also known as Arteriosclerotic Vascular Disease (ASCVD); I will use these intertwined.

Introduction

I’m writing this article after listening to a podcast episode of the Drive by Peter Attia, because I’m looking for some input from the Lesswrong community.  In this episode, #229 ‒ Understanding cardiovascular disease risk, cholesterol, and apoB, Peter highlights the importance of understanding cardiovascular disease and why early intervention is critical.

The outline of this article is as follows:

• In Part 1 I will outline why I think that this is an extremely relevant topic and I share some introductory information on atherosclerosis.
• In Part 2 I will discuss cholesterol and apolipoprotein B, which is a better, but underutilized marker of atherosclerosis.  
• In Part 3 I will introduce how atherosclerosis is diagnosed and why this seems flawed.
• In Part 4 I will introduce possible prevention strategies and I will come to the conclusion that many people might want to start statin therapy really early—like in your twenties and thirties.
• In Part 5 I will shortly highlight that this might be a surprising Effective Altruism cause. 
• I will end with my strategy going forward, discussing my personal testing, target and treatment strategy. 

I have learned a lot in writing this, but I'm still looking for some convincing arguments that help in weighing the risks involved. 

Part 1: Atherosclerosis?

Why should you care about atherosclerosis?

Let's start with some facts:

1.  It is the number one cause of death and disability in the developed world.^[1]
2. Almost everyone has sub-clinical levels of atherosclerosis. It takes about four decades for it to develop to the level that it becomes clinically significant.
3. The disease is almost completely asymptomatic until it transforms into a very serious condition. For a significant portion of people with atherosclerosis the first symptom is sudden cardiac arrest resulting in death.

To summarize it plainly: atherosclerosis is deadly, almost everyone has it and many people don't experience any symptoms until they drop dead. And those that haven't died have suffered a big blow to their health and their remaining life expectancy.

Now for the good news. Atherosclerosis is at least partly preventable and depending on who you ask, might even be fully preventable. Treatment options include medication and supplements, but also lifestyle interventions like a lipid lowering diet, regular exercise and quitting smoking.

But the current paradigm of treatment is debatable, especially at what point you should start treatment and that is exactly what this article is about.

What is atherosclerosis anyway?

Wikipedia has a good summary on this topic. So, I'm going to highlight some things from there.

Atherosclerosis is a pattern of the disease arteriosclerosis in which the wall of the artery develops abnormalities, called lesions. These lesions may lead to narrowing due to the buildup of atheromatous plaque. —Wikipedia

The progression of atherosclerosis is a complex topic with many parts, but for the casual reader I can recommend the picture below, also from Wikipedia. It summarizes the disease progression very well. Most importantly notice that it takes 4 decades for the disease to mature. 

Atherosclerosis generally starts when a person is young and worsens with age. Almost all people are affected to some degree by the age of 65.

For those of you wondering why you do not develop any symptoms even with advanced atherosclerosis:

Atherosclerosis is asymptomatic for decades because the arteries enlarge at all plaque locations, thus there is no effect on blood flow. Even most plaque ruptures do not produce symptoms until enough narrowing or closure of an artery, due to clots, occurs. Signs and symptoms only occur after severe narrowing or closure impedes blood flow to different organs enough to induce symptoms. Most of the time, patients realize that they have the disease only when they experience other cardiovascular disorders such as stroke or heart attack. These symptoms, however, still vary depending on which artery or organ is affected.

Part 2: Cholesterol and apoB

The plaque that builds up in the arterial walls is made up of cholesterol, fat, blood cells and other substances. That is why people talk about their cholesterol, when they talk about atherosclerosis, stroke and heart disease. Before we make cholesterol the absolute bad guy, it is important to keep in mind that cholesterol in itself is not problematic at all, in fact cholesterol is an essential building block for all your cells. But when it is being transported through the arteries by lipoproteins they can get stuck in your arterial walls.

Historically doctors would focus on your low-density lipoprotein cholesterol (LDL-C), because they were the best predictor for atherosclerosis. This has resulted in LDL-C being called your "bad cholesterol."

In practice when you send in your blood sample to get your LDL-C levels, they're actually testing your total cholesterol (C), your HDL-C (high density) and triglycerides (T). Using that information they estimate your LDL-C levels with a formula like this: 

Why? Because it is cheaper and as far as I understand it, it works equally well to actually measuring LDL-C.  

There is also evidence that the presence of very low-density lipoproteins (VLDL) is a factor for atherosclerosis. These particles carry mostly triglycerides and contain lower levels of cholesterol compared to LDL-C. In practice VLDL levels are hard to measure and therefore triglyceride levels are used as an indicator of VLDL due to their high triglyceride content.

This is also why there is strong evidence that it is be better to look at your non-HDL-C (total cholesterol - HDL-C), than at your LDL-C, when predicting ASCVD. 

Recently there seems to be a lot of evidence that there is a better way of measuring both VLDL and LDL-C by measuring your apolipoprotein B (apoB) levels. Lipoproteins like VLDL and LDL are complex particles build of many proteins, but they are organized by exactly one apolipoprotein B.

Where LDL-C is an indicator of the total volume of the "bad cholesterol" and the triglyceride is an indicator of the volume of the VLDL bound triglycerides, apoB is an indicator of the particle count of the LDL-C and VLDL both put together. This is great, because it seems that the count of the particles is a better predictor of ASCVD than the volume of LDL-C and triglycerides. Resulting in one number, that not only incorporates information about both particles, but also more relevant information.

To make this last point a little clearer: LDL can bind a varying amount of cholesterol, which means that the same volume of LDL-C doesn't necessarily contain the same amount of particles. The same goes for VLDL and it seems that the particle count is the better predictor of atherosclerosis than the volume.

That measuring apoB is the smarter thing to do is not controversial—at least in Europe. 

The 2019 European Society of Cardiology/European Atherosclerosis Society Guidelines concluded that apolipoprotein B (apoB) was a more accurate measure of cardiovascular risk and a better guide to the adequacy of lipid lowering than low-density lipoprotein cholesterol (LDL-C) or non-high-density lipoprotein cholesterol (HDL-C). Also, they stated that apoB can be measured more accurately than LDL-C or non-HDL-C.^[2]

In practice, if you would go to your doctor and ask them to test for your risk of atherosclerosis, it is very unlikely that they would do it by measuring your apoB levels—even in Europe. But you can ask them to measure your apoB; it is not a very expensive test, they might look at you weirdly, but they probably don't have a problem doing it.

Measuring apoB, does it really make a difference?

How much of a difference does measuring your apoB levels really make? Using that as a predictor instead of LDL-C or non-HDL-C? A Meta-Analysis of Low-Density Lipoprotein Cholesterol, Non-High-Density Lipoprotein Cholesterol, and Apolipoprotein B as Markers of Cardiovascular Risk came to the following conclusion:

We calculated the number of clinical events prevented by a high-risk treatment regimen of all those >70th percentile of the US adult population using each of the 3 markers. Over a 10-year period, a non-HDL-C strategy would prevent 300 000 more events than an LDL-C strategy, whereas an apoB strategy would prevent 500 000 more events than a non-HDL-C strategy.

The reason for this big difference is that many patients that achieve their recommended LDL-C goals still develop cardiovascular disorders, which is also known as residual risk. Apparently focusing on apoB eliminates part of that residual risk.

The Air Force/Texas Coronary Atherosclerosis Prevention Study exemplifies this perfectly in a cohort of 6605 patients. Before treatment both LDL-C and apoB are good predictors of major coronary events. After one year of treatment focused on LDL-C levels, their LDL-C levels stopped being predictive for a future major coronary event (P=.162), but their apoB levels were still a strong predictor (P=.001).^[3]

Papers mostly use LDL-C 😔

Although apoB is superior the LDL-C, most papers don't have apoB values available. In those cases I will be referring to LDL-C levels. They are highly correlated so that should be fine.

Part 3: Diagnosis

The golden standard for treatment: 10-year risk

The current standard for deciding if you need treatment is by estimating the 10-year cardiovascular risk of an individual. There are different ways of calculating this, the most popular one is the Framingham Risk Score.

Your score will give the probability that people in a similar cohort get a cardiac event within the next ten years. If this number is above a certain threshold the doctor will decide to start your treatment. For instance, the National Institute for Health and Clinical Excellence (NICE) recommends statin treatment for adults with an estimated 10 year risk that is greater than 10%.

There is an obvious flaw that comes with this standard. Your treatment will only start after you have spend the last three decades developing atherosclerosis and you're well on your way towards an arterial event. 

There do exist tools to estimate your lifetime risk, like this one and you can have a lifetime risk of 39-70% while also having a 10-year risk <10%.^[4]

Causal exposure model of vascular disease 

For a disease that takes 40 years to develop we start treatment surprisingly late and we have to wonder if earlier treatment is worth the investment. As mentioned above, there are tools to estimate your lifetime risk, but they're not used in practice. 

But before we discuss the topic of early treatment, I want to share a way of thinking about lifetime risk that is called the causal exposure model of vascular disease^[5]. The main insight of this model is that we shouldn't let the variable "age" do most of the lifting, as is the case in the current models. Instead we should estimate a large part of our risk based on the duration of exposure to negative variables. 

Specifically they're:

• level of apoB × duration of time the arterial wall is exposed to the apoB lipoproteins (this has to do with cholesterol, more on this in the next section)
• level of blood pressure × duration of time the arterial wall is exposed to blood pressure
• intensity of smoking × duration of smoking 
• duration of diabetes 
• non-modifiable risk factors due to aging

Sadly, as I understand it, this formula is a hypothetical, because the data simply isn't available to estimate the coefficients. 

There is quite some evidence that this model holds. For instance, a paper from 2006 called, Sequence Variations in PCSK9, Low LDL, and Protection against Coronary Heart Disease, looks at the presence of mutations in a gene called PCSK9 which is associated with a lowered LDL-C and apoB. Black participants had a 28 percent reduction in mean LDL-C and an 88 percent reduction in the risk of coronary heart disease^[6]. White participants had a 15 percent reduction in LDL-C and a 47 percent reduction in the risk of coronary heart disease. 

A 15% reduction in LDL-C can be considered a mild lifetime reduction in LDL-C, because treatment targets for LDL-C when patients are at risk are often far lower. To compare, the black population with a mutation had a mean LDL-C of 100mg/dL, the white population 115mg/dL and a common treatment target is 70mg/dL.

Part 4: Treatment

Indicators and targets

As we have seen in Part 3 there are four variables that you want to optimize to prevent ASCVD:

1. apoB (LDL-C)
2. blood pressure
3. diabetes
4. smoking

There is probably something to be said for adding more variables, but for the sake of simplicity and ease of use, I will leave it at this. This should capture the majority of the risk for atherosclerosis in the case of prevention.

Going forward I will only highlight what to do about apoB levels, because this is what I'm most concerned with in myself. My blood pressure is fine, I don't have diabetes and I don't smoke. If you suffer from any of these risk factors, definitely look into them.

Lifestyle Interventions 

I see three primary lifestyle interventions that are worth doing for reducing your apoB. They're worth doing even if you have a low risk of atherosclerosis, because they are generally good. They are:

• Stop smoking (I will not go into this)
• Eat healthy
• Regular exercise

Eat healthy: Introducing the Portfolio Diet

Disclaimer: I'm a little biased when it comes to this diet. Although it is among the most effective diets, there are also other diets worth exploring.  

The aim of the Portfolio Diet is to incorporate a portfolio of healthy foods into your diet that lower apoB. 

The concept of a portfolio followed the financial strategy of spreading risks and benefits over a range of options to achieve stability, and in the case of a dietary portfolio, to avoid unreasonably large doses of any single component.^[7]

I really like the concept of building a portfolio. Instead of being a fixed set of recommendations, it acknowledges that our understanding of nutrition is still in its early stages. You're literally hedging your bets! Furthermore, it leaves open the possibility that the optimal portfolio might change in the future, either by adding new categories, setting new targets or removing categories altogether. The only thing that matters is wherever the evidence points. 

Currently the Portfolio Diet consist of four categories: nuts, plant protein, vicious fibre and plant sterols. All of the foods have proven benefits on your LDL-C and apoB levels. The infographic below gives a nice summary.

Like any diet, full adherence tends to be difficult, so your results might be slightly lower. But please keep in mind, it's not all or nothing! Even incorporating parts of the diet is probably worth the investment.

Meta-analysis show that it is definitely realistic to get a 10-30% reduction in your LDL-C.^[8]

Regular exercise

I won't be going into a lot of depth here. There are many different kinds of exercise, which makes it a big topic to review. Aerobic exercise seems to work the best, but there is also plenty of evidence that strength training and yoga are helpful. 

For me the following strategy makes sense. Do whatever gets you excited to do it regularly—that is the most important thing. It is realistic to expect a 10-15% reduction in your LDL-C. 

Statins

When doctors talk about apoB lowering medication, they're mostly talking about statins. Statins are also also known as HMG-CoA reductase inhibitors, but this doesn't have the same ring to it. There are some alternatives, but this one is definitely the most popular.

There is this paper called Statin therapy for young adults: A long-term investment worth considering which makes the following remarks.

Multiple randomized control trials (RCT) performed over multiple decades have demonstrated that statin therapy for primary prevention reduces ASCVD events, including coronary revascularization, myocardial infarction, and coronary heart disease (CHD) mortality [1–4]. Subsequent meta-analyses have demonstrated strong evidence for a reduction in cardiovascular mortality with use of statin therapy [5–7], including a meta-analysis from the Cholesterol Treatment Trialists’ (CTT) Collaborators which demonstrated a 25% reduction in major vascular events (relative risk [RR] per 1.0mmol/L reduction in LDL-C, 0.75 [95% CI 0.70–0.80]), a 15% reduction in vascular mortality (RR 0.85 [95% CI 0.77–0.95]) and a 9% reduction in risk for all-cause mortality (RR 0.91 [0.85–0.97]) in individuals without established ASCVD [5].

There isn't a lot of data available on long-term use of statins in healthy adults in their 20's and 30's, but it is definitely plausible (likely) that it would increase the benefits given everything we have discussed so far.

My primary hesitation for jumping right in are the side effects of statins. The same paper has the following to say on this topic.

Despite public perception that statin therapy is associated with a high risk for side effects, when considering data from RCTs, statins have been well tolerated with an excellent safety profile [1–4], and studies with longer term follow-up have not shown any evidence of long term adverse effects [34].

So, what are the risks? I'm summarizing from the same paper here as well:

• Muscle and joint pain is most commonly reported, but there is almost no difference with the placebo groups.
• Myopathies (causes significnat muscle pain) occurs at a rate of 11 per 100,000 patient years.
• Rhabdomyolysis (serious muscle complication) occurs at a rate of 3 per 100,000 patient years.
• Developing Type II diabetes. A 9% increase in developing diabetes in trials that had an mean span of 4 years. 
• Woman that are interested in becoming pregnant should avoid using them, because this might affect their future child.

For all of these we don't know how these risks are impacted by long-term use in an otherwise healthy target audience.

These risks are serious, but they have to be put into perspective with their power to prevent death and other disabilities caused by a major vascular event. The following tradeoff definitely sounds like a good deal to me:

• I might have to take statins for the next 60 year.
• 0.66% chance of developing myopathies.
• 0.18% chance of developing rhabdomyolysis.
• 30% increase in developing diabetes type II.
• In exchange for a 50% reduction in developing major vascular events.

Is this realistic? It is plausible, but we don't know for sure because doctors don't usually offer treatment for this long. 

A big meta-analysis of 28 randomized controlled trials^[9], where the median scheduled treatment duration was 4.8 years, comes to the following conclusion:

Overall, we found a 12% (RR 0·88, 95% CI 0·85–0·91) proportional reduction in vascular mortality per 1.0 mmol/L reduction in LDL cholesterol.

Those are just the deaths prevented in the short time spans of the trials.

Side effects, alternatives and supplements

Although statins are great, surprisingly many people discontinue using them because of side effects. These side effects might occur equally often in placebo groups, but that fact doesn't seem to change much in practice. 

It is important to know there are alternatives! Although statins are the most popular form of medication, other medication does exist, for instance ezetimibe and PCSK9 inhibitors.

There are two other options that are not considered medicine, but supplements. Both are effective, seem safe and are very well tolerated by people with statin-intolerance. They're red yeast rice and burberine. 

Red yeast rice

Red yeast rice is rice overgrown with a mold culture. It apparently has been used in food preparing traditions since 300 BC. The active compounds that makes it work is monacolin K, which is chemical equivalent to lovastatin. So, red yeast rice contains one currently prescribed statin. It also contains 13 other monacolins, which appear to be less effective than monacolin K

They will lower your LDL-C and apoB by 20-30%.

There are three things to note:

1. Although they're considered safe, they might come with similar side effects to statins. Furthermore, it has been studied less intensive than statins, so there might be unknown long-term side effects. 
2. There is a lot of variability in monacolin K content between products, in a study comparing 26 brands the quantity ranged more than a 60 fold.^[10] Sadly, that same study didn't reveal what products were best.  
3. Some contain citrinin, which is a potential kidney toxin.

Berberine

Berberine is a bitter-tasting and yellow-colored chemical found in some plants, like for instance barberry. This supplement is surprisingly effective without being considered a medicine. It improves your LDL-C and apoB, but it can also be used in treating diabetes. In fact, its supposed effectiveness is comparable to the popular diabetes drug metformin. 

They will lower your LDL-C and apoB by 10-20%. Berberine might also be interesting to use in combination with a statin, since it uses a different mechanism to address the problem.

There are three things to note:

1. Although they're considered safe, they might come with side effects. Furthermore, it has been studied less intensive than statins, so there might be unknown long-term side effects. 
2. Don't use them in combination with medication for treating diabetes. It might also have interactions with a list of other medications.
3. There is a lot of variability in berberine content between products, in a study comparing 15 brands, nine of them failed to meet the potency standards. In this article you can find an overview of all the brands.

Possible recommendations for early treatment 

Statin therapy for young adults: A long-term investment worth considering gives the following advice.

As an initial step, we recommend considering both traditional and non-traditional risk factors, and calculation of lifetime risk of ASCVD with a lifetime risk ≥ 39% considered to be elevated risk [8,18,20].

The cut off point of 39% might seem a little arbitrary, but it requires you to have at least one major risk factor (smoking, stage 2 hypertension or total cholesterol 240 mg/dL).

Before we continue, let's put this into perspective.

The lifetime risk for developing clinically manifest coronary disease (angina pectoris, myocardial infarction, coronary insufficiency, or death from coronary heart disease) at age 40 years is approximately 50% for men and 32% for women.^[11]

Assuming that you have this elevated lifetime risk, they come with the following recommendations:

• In your 20's: focus on achieving and maintaining healthy lifestyle behaviors with statin use largely limited to those with evidence of familial hypercholesterolemia (genetic disorder).
• In your 30's: In addition to reinforcing the importance of healthy lifestyle behaviors, low to moderate intensity statin therapy can be offered to patients who place significant value in reducing their future ASCVD risk.
• In your 40's: For individuals at low 10-year risk, in addition to reinforcing the importance of healthy lifestyle behaviors, low to moderate intensity statin therapy to individuals who place greater value on reducing their risk and have a low disutility from statin therapy. Those hesitant, should do a Coronary Artery Calcium (CAC) test to help personalize their risk assessment. Low to moderate intensity statin therapy recommended for individuals found to have premature CAC.

Part 5: Early treatment as an EA cause?

To be honest, when I started writing this article, I hadn't planned on a Part 5 or cross posting it to the EA forum. Posting on LessWrong is scary enough. But this might be a decent EA cause. Which is funny, because when I think of foundations that are definitely not EA, I think of the Heart Foundation.

Scale

It is the number one cause of death and disability in the developed world. We're talking about 523 million cases of cardiovascular disease and 18.6 million deaths in 2019.^[1] 

Neglectedness

There are two things that are currently neglected:

1. The use of apoB as an indicator of atherosclerosis by doctors. 
2. Early treatment of atherosclerosis. The standard is to base treatment on a patients 10-year risk.

Tractability

For the majority of people the tools for preventing ASCVD already exist. We don't need to develop a cure. People in high income countries don't need funding to pay for their treatment. It's just a different treatment strategies. 

Intuitively I would guess that a campaign focused on doctors can make them start using apoB as an indicator of atherosclerosis. How much this would cost to achieve I don't know. But the threshold for changing their behavior should be incredibly low, in the case of an insured patient they only need to tick an extra box on the laboratory form. The evidence is strong for this one!

Early treatment seems much harder. Although, at this point I'm in favor of early treatment, we need clarity on this issue, there is still limited evidence. How this problem should be resolved is a complex topic, because lifetime trials are very hard to do. Even if we start today, by the time we get the results, billions might have died unnecessarily. 

My strategy going forward

Testing

I am planning to get tested on a regular basis; at least once a year, using both the standard cholesterol measurements and apoB levels, logging them carefully as they might come in handy in the future when we know more.

In periods when I'm playing around with treatment strategies, I will measure every three months to see if my strategy is working. 

In my 40s I will do a Coronary Artery Calcium (CAC) test. In the case of premature CAC I might consider more intensive treatments. 

Targets

I'm aiming for the following target:

• ApoB: ≤80mg/dL, 
• LDL-C: ≤100mg/dL.

Both will put me in the 20th Framingham Offspring Study population percentile, which is low but not that extreme. These numbers also correspond to the group that had a mutation in their PCSK9 gene which greatly reduced their risk of ASCVD. 

These are pretty ambitious targets—so I might reconsider this in the future. 

Treatment

I'm planning to do all my treatment under the supervision of my doctor. Even though I consider the treatments worth the risk, it doesn't make sense to adopt them carelessly. 

First line of defense

• Stop smoking (I don't smoke, so this is easy)
• Portfolio Diet (10 - 30% reduction, depending on adherence)
• Regular exercise, (10-15% reduction, depending on adherence)

Second line of defense

• Statins (30-70% reduction)

Or if I have too many side effect, then I can use a "natural" alternative:

• Red yeast rice (20-30% reduction)
• Berberine (10-20% reduction)

All these options are considered safe and effective, but for the natural alternatives there is only limited data available. For none of these there is long-term data available. 

There is also the option of combining statins with berberine, because berberine has a different mechanism to address the problem.

Third line of defense

If this doesn't have the preferred result, then there are further options to explore in collaboration with my doctor.

Closing remarks

I'm not an expert in this field and I wrote this article to explore my own treatment options. I can't recommend you follow my lead. I'm definitely willing to change my view on this topic, I didn't even know about it until three weeks ago. All wisdom is welcome!

1. ^{^}

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3. ^{^}

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   Berry, J. D., Liu, K., Folsom, A. R., Lewis, C. E., Carr, J. J., Polak, J. F., ... & Lloyd-Jones, D. M. (2009). Prevalence and progression of subclinical atherosclerosis in younger adults with low short-term but high lifetime estimated risk for cardiovascular disease: the coronary artery risk development in young adults study and multi-ethnic study of atherosclerosis. Circulation, 119(3), 382-389.

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6. ^{^}

   coronary heart disease (CHD) = myocardial infarction, fatal CHD, or coronary revascularization

7. ^{^}

   Jenkins, D. J., Josse, A. R., Wong, J. M., Nguyen, T. H., & Kendall, C. W. (2007). The portfolio diet for cardiovascular risk reduction. Current atherosclerosis reports, 9(6), 501-507.

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   Chiavaroli, L., Nishi, S. K., Khan, T. A., Braunstein, C. R., Glenn, A. J., Mejia, S. B., ... & Sievenpiper, J. L. (2018). Portfolio dietary pattern and cardiovascular disease: a systematic review and meta-analysis of controlled trials. Progress in cardiovascular diseases, 61(1), 43-53.

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   Armitage, J., Baigent, C., Barnes, E., Betteridge, D. J., Blackwell, L., Blazing, M., ... & Zannad, F. (2019). Efficacy and safety of statin therapy in older people: a meta-analysis of individual participant data from 28 randomised controlled trials. The Lancet, 393(10170), 407-415.

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