Peter Attia, Outlive, Cardiology 3.0 and primordial prevention of heart attacks

We are excited to bring you a review of Dr. Peter Attia's popular book Outlive from a practicing preventive cardiologist

Arguably, the most prominent “longevity doctor” in the world is now Peter Attia. His book “Outlive: The Science & Art of Longevity,” which was published a year ago has sold more than a million copies and his podcast,“The Drive” ranks among the top five in the health and fitness category on Apple and Spotify.

Many of my patients have read “Outlive” and I’ve gotten many new patient requests from individuals who believe that I practice Medicine 3.0 as envisioned by Attia in “Outlive.”

How do Attia and I align on our approach to the disease which most influences our longevity: atherosclerotic cardiovascular disease?

Peter Attia - From Surgeon to Longevity Guru

I first encountered Peter Attia online while researching ketosis, the Atkins diet and low carb diets in 2012 and found his writing to be incredibly well-researched and helpful.

When I first came across his writing he was obsessively monitoring his beta-hydroxy butyrate levels on a ketogenic diet and was partnering with Gary Taubes to launch the Nutritional Science Institute (NUSI), which they dubbed the “Manhattan project” of nutrition. Designed to help fund good nutritional research with the ultimate goal of reducing obesity and testing the hypothesis that “all calories are equal,” NUSI, unfortunately has floundered and is dead.

I appreciated how Attia never opted for oversimplification of a topic; he was rigorous in his thinking and writing in the areas of nutrition, diet and longevity and was knowledgeable down to very basic areas of biology and metabolism.

In 2019 I wrote enthusiastically about his new podcasts in a post entitled “The Peter Attia Drive Podcast: Longevity, Lipidology, Fructose, and How To Keep Your Face And Joints Young.”

As a cardiologist with a keen interest in preventing complications of atherosclerosis (ASCVD), I was particularly excited that one of his earliest podcast series was with Thomas Dayspring, M.D., FACP, FNLA, a world-renowned expert in lipidology. If you’d like to dive deeply into cholesterol metabolism, lipid biomarkers, the mechanism of atherosclerosis and cholesterol treatment options, this podcast is a great way to start.

The Ticker: Atherosclerosis and Coronary Calcium

Chapter 7 of Attia’s book deals with heart disease, the “deadliest killer on the planet.”

He begins the chapter by describing a strong history of premature coronary artery disease (CAD) in his family: 3 uncles had heart attacks in their 40s and his father underwent coronary stenting.

With this background, he correctly concludes that despite having very low conventional risk factors he was likely to die from CAD. (Something we address here.)

Thus, at age 36, he insisted that his doctor order a coronary calcium scan, which came back with a calcium score of 6. Given that the range of calcium scores goes from zero to several thousand this may seem low but for any individual under age 40, this is a sign of markedly advanced subclinical atherosclerosis.

Attia knew that by the time calcium appears in the lining of the coronary arteries, atherosclerosis has been brewing for many years and he thus began a "yearlong quest" to change his trajectory.

Fortunately for him he gained access to some of the leading scientific minds in lipidology including Ron Krauss, Allan Sniderman, and Tom Dayspring. These doctors became his mentors in preventive cardiology.

Thanks to this good input, in several sections of the Ticker chapter, he accurately and vividly describes how the atherosclerotic process occurs and why it is related to the levels of LDL cholesterol in the blood. He also correctly identifies apolipoprotein B (apoB) as the major particle responsible for triggering atherosclerosis—a process which begins when an apoB LDL particle sticks in the arterial wall and becomes oxidized.

Pages 119 through 125 do a great job of explaining how atherosclerosis develops insidiously in the coronary arteries and how you can build up substantial plaque without symptoms.

The small amount of calcium that was identified in his coronaries at age 36 are a marker for his body trying to repair this damage. Attia notes this is like "pouring concrete on the Chernobyl reactor: you're glad it's there but you know there's been an awful lot of damage in the area to warrant such an intervention."

I also fully endorse this line: "A positive calcium score is really telling us that there are almost certainly other plaques around that may or may not be stabilized (calcified)."

Risk Factors For Coronary Heart Disease

Attia is famously an obsessive fitness freak, so it is hard for most people to fathom how he developed such marked subclinical ASCVD at a young age. He felt that he had accumulated visceral fat and was insulin-resistant.

His LDL-C was "110 to 120 mg/dl," which is not particularly high. His triglycerides were slightly elevated. He now knows these numbers indicate high levels of apoB "but no one bothered to test my apoB number."

He feels that he had "all three of the major prerequisites for heart disease: that is, a significant apoB burden plus LDL oxidation plus a high level of background inflammation. 

Attia:

None of these is enough to guarantee that someone will develop heart disease, but all three are necessary to develop it.

At this point, Attia rightfully spends a few pages talking about lipoprotein (a), something I've covered in detail here and here. I agree with him that this inexpensive blood test should be checked on all individuals at least once.

How to Reduce Cardiovascular Risk

Attia writes that there are three blind spots of Medicine 2.0¹ when it comes to dealing with ASCVD:

• An overly simplistic view of lipids that fails to understand the importance of total lipoprotein burden (apoB) and how much one needs to reduce it in order to truly reduce risk

• Lack of knowledge about "other bad actors" such as Lp(a)

• Failure to fully grasp the lengthy time course of ASCVD—and the implications this carries if “we seek true prevention."

I agree that doctors don’t reach levels of apoB and LDL-C adequate enough to prevent or mitigate ASCVD. I also agree that doctors are not testing for Lp(a) and apoB enough. These are essential components of modern preventive cardiology.

However, I think the vast majority of physicians do understand the importance of LDL-C levels (which are concordant with apoB 90% of the time and are tightly related to the non-HDL fraction of total cholesterol) in the development of ASCVD.

Attia’s third "blind spot of Medicine 2.0" is a failure to recognize the early onset and prolonged time course of atherosclerosis. Medicine 3.0 practitioners, he writes, should be much more aggressive at lowering apoB and should start as early as possible. They should not be guided by the patient's 10-year risk of ASCVD but consider their lifelong or 30-year risk.

To illustrate this point he notes that current guidelines would recommend treating a 74-year-old man with low apoB (who will invariably have a high calculated 10-year risk) but not a 45-year-old man with high apoB (whose 10-year risk will be quite low unless LDL is >180 mg/dl.)

Medicine 3.0 says “to disregard the ten-year risk and instead treat the causal agent… in both cases-lowering the 45-year-old's apoB as much as possible."

This is an excellent point and one which exposes the limitations of current guidelines, which use standard risk factors and pooled cohort equations to estimate individual 10-year risk to guide the aggressiveness of therapy. (I discuss this limitation in depth in my last post.)

I've discussed in detail how I approach ASCVD risk assessment and treatment in younger individuals. I believe that we have to look beyond standard risk assessment and management tools in younger individuals.

Attia's Super-Aggressive Recommendations Lack Scientific Support

At this point, Attia moves from what has been definitely proven in this area and into a speculative zone.

To support his Medicine 3.0 thesis—that we should be lowering the elevated apoB of a 45 year old man "as much as possible”—he cites a 2019 article written by Peter Libby, an esteemed leader in the fields of vascular biology, atherosclerosis and preventive cardiology:

“Atherosclerosis probably would not occur in the absence of LDL-C concentrations in excess of physiological needs (on the order of 10 to 20 mg/dl).

If the entire population maintained LDL concentrations akin to those of a neonates (or to those of adults in most other animal species) atherosclerosis might well be an orphan disease."²

Apparently, in Attia's practice, "this is my starting point with any patient. We want it as low as possible, sooner rather than later."

I emphasize that these are speculations. They are unproven. And I am unaware of any cardiologists who practice this approach. Despite Peter Libby's musings on the value of low LDL-C levels, at no point does he suggest that we should be using multiple cholesterol-lowering drugs to achieve neonatal levels of LDL.

LDL-C Targets Are Moving Downward

Recent evidence has accumulated supporting lower LDL-C targets for many patient groups.

The 2018 American guidelines recommend an LDL-C level <100 mg/dl for primary prevention. For patients with established ASCVD (secondary prevention) they recommend LDL-C <70.  In September 2019, the European Society of Cardiology (ESC) and European Atherosclerosis Society (EAS) published a new guideline and introduced updated recommendations, including recommending that LDL-C be lowered as much as possible, specifically a goal of <1.4 mmol/L (<55 mg/dL) in patients who are at very high risk for cardiovascular events.

In 2022, an American College of Cardiology Expert Consensus Decision Pathway endorsed an LDL goal of <55 mg/dl (<85 mg/dl for non-HDL levels³⁾ in very high risk secondary prevention patients.

I have long aimed for LDL-C and apoB levels/non HDL levels <60 in my patients with documented ASCVD (either by CAC, CCTA or ASCVD events). I keep my own apoB and LDL-C levels in the 40s.

But an LDL-C goal of 10-20 mg/dl is really, really (almost unrealistically) low. To achieve levels <20, most individuals would require multiple cholesterol-lowering medications each with a potential for side effects and a significant cost.

Attia acknowledges this:

"For many patients, if not for most, lowering apoB to the levels we aim for...cannot be accomplished with diet alone, so we need to use nutritional interventions in tandem with drugs."

Primordial Prevention

At this point Attia discusses the concept of primordial prevention of ASCVD.

While primary prevention is about treating risk factors to prevent cardiovascular disease, primordial prevention is about preventing risk factors in the first place. Scientists say primordial prevention is a term that refers to lifestyle and diet interventions early in childhood that modify the development of obesity, diabetes, and atherosclerosis in adulthood.³

It is clear, however, that for some high-risk individuals, more aggressive interventions, including initiating cholesterol-lowering therapy at an early age, could be much more effective in preventing ASCVD lifelong.

Attia cites an Allan Sniderman 2018 JAMA paper to support the effectiveness of this approach:

…most physicians and cardiology experts would still insist that one's thirties are too young to begin to focus on primary prevention of cardiac disease. This viewpoint is directly challenged by a 2018 JAMA Cardiology paper coauthored by Allan Sniderman, comparing ten-year versus thirty-year risk horizons in terms of prevention. Sniderman and colleagues' analysis found that looking at a thirty-year time frame rather than the standard ten years and taking aggressive precautionary measures early-like beginning statin treatment earlier in certain patients could prevent hundreds of thousands more cardiac events, and by implication could save many lives.

For context, most studies of statins used in primary prevention (that is, prevention of a first cardiac event) last about five years and typically find a "number needed to treat" (or NNT, the number of patients who need to take a drug in order for it to save one life) of between about 33 and 130, depending on the baseline risk profile of the patients.

(Amazingly, the longest statin trials to date have lasted just seven years.) But looking at their risk reduction potential over a thirty-year time frame, as the Sniderman study did, reduces the NNT down to less than 7: For every seven people who are put on a statin at this early stage, we could potentially save one life.

It should be noted that this was a theoretical estimate based on re-analysis of NHANES data. Such an approach would result in millions of individuals taking a statin drug their entire life that they would not benefit from. A randomized trial of this approach has not been performed.

My Summary

Attia gets a lot of things right in his Ticker chapter.

• He focuses on atherosclerosis and identifies elevated apoB/LDL-C as the main cause and treatable target.

• He emphasizes the need for early identification and treatment of subclinical ASCVD.

• He advocates for early and aggressive treatment of elevated apoB

• He has a good discussion on statin and non-statin therapies.

I feel he strays too far from the science, however, when he advocates for LDL-C goals of <20 mg/dl seemingly for all individuals, irrespective of their overall lifetime risk of cardiovascular disease. Achieving these goals would require multiple different cholesterol-lowering medications.

Recently, Attia revealed that he is taking 3 different cholesterol medications, Bempedoic Acid, ezetimibe and a PCSK9 inhibitor. This is the kind of cocktail that would be needed to get his patients to the goal he recommends.

For many individuals at a low to moderate lifetime risk of ASCVD this makes little sense. There would be very little benefit from reduction of ASCVD risk at a substantial financial cost and at the risk of significant side effects.

Furthermore, Attia is suggesting lifetime treatment for two of the three drugs he takes (and presumably prescribes). We don't have data beyond 5-10 years on long-term side effects.

Attia ends his chapter with a discussion on cholesterol-lowering medications. I'll discuss this section and the specific drugs he is taking in a subsequent post.

He very briefly touches on diet and ASCVD in this chapter of his book. Like me, he has a low opinion of nutritional epidemiology. In future posts, we'll delve into what I think he gets right and where he errs in his nutritional advice.

Outlivingly Yours,

-ACP

N.B.

(1). Attia calls the era exemplified by Hippocrates and lasting for 2000 years after his death Medicine 1.0. Conclusions were based on directional observation and pure guesswork. Sometimes they got things right, but most of the time they got things wrong. Medicine 2.0 for Attia begins in the mid-nineteenth century with the advent of germ theory of disease and the development of the scientific method which was transformational. Medicine 3.0, he writes, is focused on the prevention of chronic diseases such as ASCVD, cancer and Alzheimer's.

(2) The first sentence Attia cites is from the following paragraph in Libby's 2019 Nature Review article entitled "Atherosclerosis"

Atherosclerosis probably would not occur in the absence of LDL-C concentrations in excess of physiological needs (on the order of 10–20 mg/dL)⁸. Phylogenetic, comparative population studies and pharmacological intervention investigations suggest that LDL-C concentrations in the 20–30 mg/dL range (about 0.5–0.8 mmol/L) suffice for good health^8,9,10,11. Hence, despite recent secular trends towards lowering cholesterol levels, the concentrations of blood cholesterol prevalent in most contemporary human societies exceed by far the biological needs of the organism, and permit the development of atherosclerosis^12,13. The cumulative exposure of an artery to LDL-C over years remains a principal determinant of disease initiation and progression¹⁴. 

The second sentence which Attia implies is from the "Atherosclerosis" paper is not in that paper. The Notes section at the back of his book cites a 2021 paper first-authored by Libby. The closest sentence I can find in that paper is below

Successive studies with statins have addressed individuals with progressively lower risks, and the development of more potent statins has led to the ability to drive LDL concentrations even lower. The ensemble of large-scale clinical trials with statins firmly established the benefits of LDL lowering. The results fostered the concept of ‘lower is better.’ Moreover, the safety profile of this class of agents demonstrated that low concentrations of LDL, more akin to those of a human neonate or many animal species, did not entail adverse consequences.

Note that Libby does not claim we should be targeting LDL-C reduction to <20 mg/dl. In fact, at the end of this 2021 paper he writes:

The application of PCSK9 therapeutics has plumbed the depths of LDL-C achievable in practice. Thus, further lowering of LDL-C beyond that achievable by combinations of current treatments, including PCSK9-blocking strategies, may not yield appreciable increments in cardiovascular benefits¹⁹. Hence, we welcome the development and clinical evaluation of orthogonal approaches to cardiovascular-risk reduction, such as targeting other atherogenic lipids or quelling inflammation. 

3 The Special Turku Coronary Risk Factor Intervention Project (STRIP) Circulation. 2015 is the best example of the conventional approach to primordial prevention.