A Closer Look Into Preventing and Treating ASCVD
I love thinking about how we can each improve our own healthspan- the length of time during which we can live independently in relatively good health. Most of you already know that my thinking is heavily influenced by Peter Attia, MD, including the concepts in his book, “Outlive.” And I know that many of you have also read this book.
So I will only briefly summarize one core concept of improving healthspan, which is that we must limit, to the best of our capabilities, any risks for chronic disease, namely heart disease, metabolic disease (i.e., insulin resistance), cancer, and cognitive decline.
I’m writing this to share a few thoughts on cardiovascular disease, because this is the leading cause of death in the United States, and in more cases than not, it can be prevented.
In this context, cardiovascular disease specifically refers to atherosclerotic cardiovascular disease (ASCVD), which includes heart attack and stroke.
What is ASCVD?
Atherosclerosis essentially means that lipoproteins (or what we more simply, albeit somewhat inaccurately, call cholesterol) build up on artery walls. These lipoproteins, along with other inflammatory cells, can eventually form plaques on the artery walls. Those plaques cause narrowing of the vessels, limiting the flow of blood, and they can sometimes rupture, allowing a piece of the plaque to completely occlude a narrower part of the downstream artery, and thus cut off blood supply to the tissue (i.e., heart muscle or brain in heart attack and stroke, respectively).
This means that heart attacks and strokes occur from plaque formation, that has typically taken place over the prior few decades.
While conventional medicine sends a clear message that (1) high cholesterol is bad, (2) anyone with a cholesterol level over 190 should be on a statin, and (3) statins are always good, most of you understand there is more nuance, and many of you are even skeptical that this message is accurate.
I believe that treatment approaches always need to be individualized and that we need to take a careful look at our own risk factors. So here I want to explain in more detail why I think LDL lowering therapy is worth considering for some individuals and I hope the discussion below will help to provide a framework for you to think about your own cardiovascular health.
Lab Markers
The following list comprises the lab markers that may be used in thinking about your risk of ASCVD:
HDL
Limited usefulness. While a low HDL may slightly increase my concern about ASCVD risk, a high HDL is not always good. I think there might be more we don’t know about HDL than what we do know.
LDL-calc
This is what you will see in a standard lipid panel, it is a calculated (i.e., grossly estimated) LDL, and I find very little value in a calculated LDL level. But a standard lipid panel is cheap, so this can still be a good place to start screening, particularly when we’re working with a more limited budget.
Apolipoprotein B
Currently my single favorite marker for assessing ASCVD risk. Apolipoprotein B (apoB) is essentially a protein tag on all the lipoproteins that may contribute to atherosclerosis (i.e., plaque formation). So apoB will reflect a measurement of low density lipoproteins (LDL), but also intermediate density lipoproteins (IDL) and very low density lipoproteins (VLDL), providing a more accurate measure of atherogenic lipoprotein particles. Because LDL particles make up about 90 to 95% of apoB-containing lipoproteins, I will sometimes use the phrase LDL lowering interchangeably with apoB lowering.
Lipoprotein (a), or Lp(a)
This is a circulating lipoprotein with the level determined largely by genetics. High levels of Lp(a) may increase the risk of ASCVD, so in people with high Lp(a) I prefer more ambitious LDL lowering goals. I think it is helpful to measure this at least once, but at this time I’m not clear on the benefit of follow up measurements.
Lipoprotein fractionation
This allows us to see the LDL and HDL particle numbers, along with more detail about particle size. LDL particles can be like big, fluffy, bouncy balls that are less likely to damage the arterial walls, or they can be more like small dense golf balls, which more easily wedge into the vessel wall and cause injury. I think lipoprotein fractionation can be a nice contribution to understanding ASCVD risk, but it is rarely covered by insurance. So when we want to prioritize budget, then we can often leave this out.
C-reactive protein, high sensitivity, or CRP-hs
This is a marker of inflammation, though a non specific marker. I always prefer to see this less than 1.0, and if someone has a persistently elevated CRP-hs, which may be correlated with an increased risk of ASCVD, then I would like to consider more ambitious lipoprotein lowering goals.
Homocysteine
This is an amino acid that is an intermediary in a particularly useful and common biochemical cycle called the methylation cycle. The methylation cycle occurs in all of our cells essentially constantly. When homocysteine levels are elevated, clearly above 11 and maybe even above 9, there is a correlation with an increased risk of ASCVD, cognitive decline and cancer. So while I like to see everyone’s homocysteine level below 9, when it is above 9 I give stronger consideration to LDL lowering.
For completeness, when we are thinking about ASCVD risk we may also take into account:
Blood pressure
Glycemic control (i.e., blood sugar balance and insulin sensitivity/resistance)
Current or prior smoking
Family history of heart attack or stroke
Optionally, coronary artery calcium (CAC) score or plaque seen on a coronary angiogram
So why did I just go into all that detail?
There are so many extremes out there. Some cardiologists recommend putting statins in the water, and purport that there is no such thing as a cholesterol value that is too low. And others, often in the ketogenic diet or carnivore communities, may claim that high LDL in the context of a low carbohydrate diet is nothing to worry about.
And amidst these strong opinions, even with all the knowledge around ASCVD and advanced imaging technologies, we still cannot accurately predict who will go on to develop ASCVD. So how do you decide what’s right for you?
In essence, I think of ASCVD as a probability. With a high apoB there are more circulating atherogenic lipoproteins, and thus a higher probability that those apoB containing particles will encounter an area of an artery where they may accumulate and start the process of plaque formation. Again, serious plaque formation most often takes multiple decades. So the longer you have high apoB, the higher that apoB is, then the higher the probability those apoB particles are making their way into plaques.
If you add in a high Lp(a) and high CRP-hs, then our probability goes up even further.
So depending on your risk factors, we might look to target your apoB to between 60 to 80. Most people are going to benefit from prescription lipid lowering therapy to achieve these goals.
Options to Lower Your apoB
Statins
There are currently eight different statins approved by the FDA. These are cheap, generally very effective, and most often very well tolerated. That said, the side effects with statins include a risk of muscle pain and weakness, elevated liver enzymes, a potential risk of insulin resistance, and in a subset of patients an increased risk of cognitive decline. To possibly help decrease the risk of cognitive decline, I like to work primarily with two statins, rosuvastatin and pravastatin, which are thought to be less likely to cross the blood brain barrier, and thus less likely to interfere with cholesterol synthesis in the brain (where cholesterol is very important). Statins also interfere with mitochondrial function, but it’s not clear to what extent and in some people this may be minimal. Taking a CoQ10 supplement (in the form of ubiquinol), may help to offset potential mitochondrial dysfunction.
Ezetimibe
Ezetimibe is another inexpensive medication that may not be as potent as statin therapy, but may be better tolerated. While statins affect cholesterol production, ezetimibe decreases cholesterol absorption in the small intestine.
If your apoB is high and you’re considering a prescription medication to lower your apoB, then I often like to run the Boston Heart Labs Cholesterol Balance test, which measures four sterols. Two of the sterols relate to cholesterol production, and two relate to cholesterol absorption. Depending on which of the sterols are elevated, we can see if your high apoB relates more to cholesterol production or cholesterol absorption. If your markers of cholesterol absorption are high, then ezetimibe might be a particularly good option.
I often find that ezetimibe and statins work particularly well together, and if someone has concerns with statin therapy, then a combination of ezetimibe taken daily, with rosuvastatin or pravastatin taken just three days per week, might allow for significant LDL lowering while also limiting statin exposure.
PCSK9 Inhibitors
PCSK9 inhibitors are a newer class of LDL lowering medications. These are monoclonal antibodies, currently available as injections. PCSK9 inhibitors prevent the PCSK9 proteins from their normal work of degrading LDL receptors. This leaves more LDL receptors available to bind LDL particles and remove them from circulation. These are very potent at lowering LDL and for some people may be better tolerated than statins. That said, unless there is a clear intolerance to all statins, in which case insurance may cover a PCSK9 inhibitor, these run about $500 per month.
Bempedoic Acid
Bempedoic acid is another LDL lowering medication that seems to be very well tolerated. It’s actually a prodrug that is ineffective until metabolized in the liver, so unlike statins that inhibit cholesterol synthesis throughout the body, bempedoic acid only inhibits cholesterol synthesis in the liver (the primary source of circulating lipoproteins). But again, without insurance coverage the cost is currently about $500 per month.
By being more aware of these lab markers, various treatment protocols and the nuances around each one, you can work with your doctor to create a plan that can result in preventing and/or treating ASCVD and increasing your healthspan. Remember that the approach you take to increasing your healthspan will be unique to you.
*Medical Disclaimer: This article does not constitute as medical advice. Always consult with your physician before taking any steps to alter current treatment plans or begin new ones.