summarize this "In a way, Not-Thin Peter and Anahad O’Connor were like two sides of the
same coin. While our stories don’t seem to have much in common, both
underscore the insidious, almost sneaky nature of heart disease: my risk
should have been obvious, based on my family history, while Anahad’s
disease remained all but invisible until he happened to have a calcium scan,
which is not normally done on healthy-seeming people in their thirties. We
only learned of our risk thanks to dumb luck, because few doctors would have
considered screening either of us for heart disease at our ages.
Together, our stories illustrate three blind spots of Medicine 2.0 when it
comes to dealing with atherosclerotic disease: first, 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;
second, a general lack of knowledge about other bad actors such as Lp(a);
and third, a failure to fully grasp the lengthy time course of atherosclerotic
disease, and the implications this carries if we seek true prevention.
When I look at a patient’s blood panel for the first time, my eyes
immediately dart to two numbers: apoB and Lp(a). I look at the other
numbers, too, but these two tell me the most when it comes to predicting
their risk of ASCVD. ApoB not only tells me the concentration of LDL
particles (which, you’ll recall, is more predictive of disease than the
concentration of cholesterol found within LDL particles, LDL-C), but it also
captures the concentration of VLDL particles, which as members of the apoB
family can also contribute to atherosclerosis. Furthermore, even someone
whose apoB is low can still have a dangerously elevated Lp(a).
[*6]
Once you establish the central importance of apoB, the next question
becomes, By how much does one need to lower it (or its proxy LDL-C) to
achieve meaningful risk reduction? The various treatment guidelines specify
target ranges for LDL-C, typically 100 mg/dL for patients at normal risk, or
70 mg/dL for high-risk individuals. In my view, this is still far too high.
Simply put, I think you can’t lower apoB and LDL-C too much, provided
there are no side effects from treatment. You want it as low as possible.
As Peter Libby, one of the leading authorities on cardiovascular disease,
and colleagues wrote in Nature Reviews in 2019, “Atherosclerosis probably
would not occur [emphasis mine] in the absence of LDL-C concentrations in
excess of physiological needs (on the order of 10 to 20 mg/dL).”
Furthermore, the authors wrote: “If the entire population maintained LDL
concentrations akin to those of a neonate (or to those of adults of most other
animal species), atherosclerosis might well be an orphan disease.”
Translation: if we all maintained the apoB levels we had when we
were babies, there wouldn’t be enough heart disease on the planet for people
to know what it was. Kind of like 3-hydroxyisobutyric aciduria. What, you
haven’t heard of it? Well, that’s because there have been only thirteen
reported cases. Ever. That is an orphan disease. I’m being a bit facetious, but
my point is that atherosclerotic disease shouldn’t even be in the top ten causes
of death, if we treated it more aggressively. Instead, we have over eighteen
million cases of fatal atherosclerotic disease per year globally.
Many doctors, and in fact many of you reading this, might be shocked to
see such a low LDL-C target: 10 to 20 mg/dL? Most guidelines consider
lowering LDL-C to 70 mg/dL to be “aggressive,” even for secondary
prevention in high-risk patients, such as those who have already had a heart
attack. It’s also natural to ask whether such extremely low levels of LDL-C
and apoB are safe, given the ubiquity and importance of cholesterol in the
human body. But consider the following: infants, who presumably require the
most cholesterol, in order to meet the enormous demands of their rapidly
growing central nervous system, have similarly low levels of circulating
cholesterol, without any developmental impairment. Why? Because the total
amount of cholesterol contained in all our lipoproteins—not just LDL, but
also HDL and VLDL—represents only about 10 to 15 percent of our body’s
total pool of cholesterol. So the concern is unwarranted, as demonstrated by
scores of studies showing no ill effects from extremely low LDL
concentrations.
This is my starting point with any patient, whether they are like Anahad
(with one prominent risk factor) or like me (lots of smaller risk factors). Our
first order of business is to reduce the burden of apoB particles, primarily
LDLs but also VLDLs, which can be dangerous in their own right. And do so
dramatically, not marginally or incrementally. We want it as low as possible,
sooner rather than later. We must also pay attention to other markers of risk,
notably those associated with metabolic health, such as insulin, visceral fat,
and homocysteine, an amino acid that in high concentrations
[*7] is strongly
associated with increased risk of heart attack, stroke, and dementia.
You’ll note that I don’t pay much attention to HDL-C, because while
having very low HDL-C is associated with higher risk, it does not appear to
be causal. This is why drugs aimed at raising HDL-C have generally failed to
reduce risk and events in clinical trials. The reasons why are suggested by two
elegant Mendelian randomization studies that examined both sides of the
HDL-C question: Does low HDL-C causally increase the risk of myocardial
infarction? No. Does raising HDL-C causally lower the risk of myocardial
infarction? No.
Why? Probably because whatever benefit HDLs provide in the battle for
arterial supremacy, it (again) seems to be driven by their function—which
doesn’t seem to be related to their cholesterol content. But we cannot test for
HDL functionality, and until we have a better grasp on how HDL actually
works, it will likely remain elusive as a target of therapy.
—
Lipoproteins aren’t the only significant risk factors for cardiovascular disease;
as noted earlier, smoking and high blood pressure both damage the
endothelium directly. Smoking cessation and blood pressure control are thus
non-negotiable first steps in reducing cardiovascular risk.
We’ll talk about nutrition in much more detail, but my first step in
controlling my own cardiovascular risk was to begin to change my own diet,
so as to lower my triglycerides (a contributor to apoB when they are high, as
mine were), but more importantly to manage my insulin levels. I needed to
get my metabolic house in order. I should note that my own solution at the
time, a ketogenic diet, might not work for everyone, nor is it a diet to which I
continue to adhere. In my clinical experience, about a third to half of people
who consume high amounts of saturated fats (which sometimes goes hand in
hand with a ketogenic diet) will experience a dramatic increase in apoB
particles, which we obviously don’t want.
[*8] Monounsaturated fats, found in
high quantities in extra virgin olive oil, macadamia nuts, and avocados
(among other foods), do not have this effect, so I tend to push my patients to
consume more of these, up to about 60 percent of total fat intake. The point
is not necessarily to limit fat overall but to shift to fats that promote a better
lipid profile.
But for many patients, if not for most, lowering apoB to the levels we aim
for—the physiologic levels found in children—cannot be accomplished with
diet alone, so we need to use nutritional interventions in tandem with drugs.
Here we are fortunate because we have more preventive options in our
armamentarium than we do for cancer or neurodegenerative disease. Statins
are far and away the most prescribed class of drugs for lipid management, but
there are several other options that might be right for a given individual, and
often we need to combine classes of drugs, so it’s not uncommon for a patient
to take two lipid-lowering drugs that operate via distinct mechanisms. These
are typically thought of as “cholesterol-lowering” medications, but I think we
are better served to think about them in terms of increasing apoB clearance,
enhancing the body’s ability to get apoBs out of circulation. That’s really our
goal. Mostly this is done by amplifying the activity of LDL receptors (LDLR)
in the liver, which absorb cholesterol from the bloodstream.
Different drugs arrive at this effect via different paths. Typically our first
line of defense (or attack), statins inhibit cholesterol synthesis, prompting the
liver to increase the expression of LDLR, taking more LDL out of
circulation. They may have other benefits too, including an apparent anti-
inflammatory effect, so while I don’t think statins should be dissolved into the
drinking water, as some have suggested, I do think they are very helpful drugs
for reducing apoB or LDL concentration in many patients. Not everyone can
take statins comfortably; about 5 percent of patients experience deal-breaking
side effects, most notably statin-related muscle pain. Also, a smaller but
nonzero subset of patients taking statins experience a disruption in glucose
homeostasis, which may explain why statins are associated with a small
increase in the risk for type 2 diabetes. Another fraction of patients
experience an asymptomatic rise in liver enzymes, which is even more
common in patients also taking the drug ezetimibe. All these side effects are
completely and rapidly reversible when the drug is discontinued. But for those
who can tolerate them (i.e., most people), I deploy them early and often. (For
more on specific statin and other apoB-lowering medications, see the sidebar
on this page.)
—
This brings us to the final, and perhaps greatest, major blind spot of Medicine
2.0: time.
The process I’ve outlined in this chapter unfolds very slowly—not over
two or three or even five years, but over many decades. The fact that younger
people have been found to have lesions and plaques, without suffering many
events, tells us that there is a considerable period of time when the disease is
not harmful. Dying from cardiovascular disease is certainly not inevitable: the
centenarians delay it for decades, and many avoid it altogether, their arteries
remaining as clean as those of people a generation younger. Somehow, they
manage to slow the process down.
Nearly all adults are coping with some degree of vascular damage, no
matter how young and vital they may seem, or how pristine their arteries
appear on scans. There is always damage, especially in regions of shear stress
and elevated local blood pressure, such as curves and splits in the vasculature.
Atherosclerosis is with us, in some form, throughout our life course. Yet most
doctors consider it “overtreatment” to intervene if a patient’s computed ten-
year risk of a major adverse cardiac event (e.g., heart attack or stroke) is
below 5 percent, arguing that the benefits are not greater than the risks, or
that treatment costs too much. In my opinion, this betrays a broader
ignorance about the inexorable, long-term unfolding of heart disease. Ten
years is far too short a time horizon. If we want to reduce deaths from
cardiovascular disease, we need to begin thinking about prevention in people
in their forties and even thirties.
Another way to think of all this is that someone might be considered “low
risk” at a given point—but on what time horizon? The standard is ten years.
But what if our time horizon is “the rest of your life”?
Then nobody is at low risk.
When I had my first calcium scan in 2009, at the age of thirty-six, my tenyear risk was incalculably low—literally. The dominant mathematical models
for risk assessment have a lower limit for age of forty or forty-five. My
parameters could not even be entered into the models. So it’s no wonder
nobody was alarmed by my findings. Despite my calcium score of 6, my tenyear risk of a heart attack was far less than 5 percent.
In 2016, seven years after my initial calcium scan, I had a CT angiogram
(the better, higher-res scan), which showed the same small speck of calcium
but no evidence of additional soft plaque elsewhere. In 2022, I went back
again for a repeat CT angiogram, and the result was the same. There was no
indication whatsoever of soft plaque this time either, and only that tiny speck
of calcium remained from 2009.
[*9] Thus, at least at the resolution of the
sharpest CT scanner commercially available, there is no reason to believe that
my atherosclerosis has progressed over thirteen years.
I have no idea if this means I’m free from risk—I frankly doubt it—but I
no longer fear dying from cardiovascular disease the way I once did. My long,
comprehensive program of prevention seems to have paid off. I feel a lot
better now, at age fifty, than I did at age thirty-six, and my risk is a lot lower
by any metric other than age. One major reason for this is that I started early,
well before Medicine 2.0 would have suggested any intervention.
Yet 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. The reason for
this is simple math: risk is proportional to apoB exposure over time. The
sooner we lower apoB exposure, thus lowering risk, the more the benefits
compound over time—and the greater our overall risk reduction.
This encapsulates the fundamental difference between Medicine 2.0 and
Medicine 3.0 when it comes to cardiovascular disease. The former views
prevention largely as a matter of managing relatively short-term risk.
Medicine 3.0 takes a much longer view—and more importantly seeks to
identify and eliminate the primary causative agent in the disease process:
apoB. This changes our approach to treatment completely. For example, a
forty-five-year-old with elevated apoB has a lower ten-year risk than a
seventy-five-year-old with low apoB. Medicine 2.0 would say to treat the
seventy-five-year-old (because of their age), but not the forty-five-year-old.
Medicine 3.0 says to disregard the ten-year risk and instead treat the causal
agent in both cases—lowering the forty-five-year-old’s apoB as much as
possible.
Once you understand that apoB particles—LDL, VLDL, Lp(a)—are
causally linked to ASCVD, the game completely changes. The only way to
stop the disease is to remove the cause, and the best time to do that is now.
Still struggling with this idea? Consider the following example. We know
that smoking is causally linked to lung cancer. Should we tell someone to stop
smoking only after their ten-year risk of lung cancer reaches a certain
threshold? That is, do we think it’s okay for people to keep smoking until they
are sixty-five and then quit? Or should we do everything we can to help young
people, who have maybe just picked up the habit, quit altogether?
When viewed this way, the answer is unambiguous. The sooner you cut
the head off the snake, the lower the risk that it will bite you.
"