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February 24, 2020

What do you do if you have tried everything as discussed so far and have not achieved a sufficient reduction in your risk through lowering your number of LDL hypothetical cars in circulation and/or also have issues with inflammation residually?

This is the intersection where lifestyle changes meet medicine needs. There are some instances where, in 2020, we are still dependent on medicine to help us stay alive despite our best attempts otherwise. Again, I turn to the experts for an understanding of the medicines and their role in disease. Sometime this year I will take a look, this will not be an exhaustive look at all of the medicines, but more a tour through the most beneficial to date.

This section is technical but excellent for a thorough understanding of risk and therapy. Skip it if you don't want the science.

Ok. You are in your mid-forties or fifties and the above scenario fits you. I think that the first and most important thing to do is ascertain your current risk. In an excellent two-part series recently, Dr. Peter Attia laid out the case for measuring a specific particle called apolipoprotein B and/or LDL particle size instead of total LDL cholesterol levels which is currently the chosen test. Apolipoprotein B is a signaling and a structural protein found on the cell surface of the lipoprotein cars known as chylomicrons, VLDL, IDL, Lp(a) and LDL. It is much more highly associated with coronary vascular events.

Per Dr. Attia: "Important in understanding why lipidologists like Dr. Sniderman are increasingly arguing for more direct measurements of the number of lipoproteins themselves, rather than the cholesterol or triglycerides contained within them, is the concept of concordance and discordance. The most common scenario in which we can examine this concordance/discordance split is contrasting LDL-C (the commonly used measure of cholesterol contained within LDL) and LDL-P (the less commonly used measure of the number of LDL particles).

A high level of LDL-C predicts a high level of LDL-P. Same for low LDL-C predicting low LDL-P. When LDL-C and LDL-P agree, they are said to be concordant, and they equally predict the same outcome: both are high (or low) relative to the population. When they disagree-one is high and one is low-they are said to be discordant. (Note: we're not talking about comparing the absolute numbers of either metric-they are measuring different things in different units-we're talking about how each stacks up to their respective population mean.)

When LDL-C is concordant with LDL-P, LDL-C is a fine predictor of adverse cardiovascular events. But when there's discordance, it's imperative to know which-LDL-C or LDL-P-is the correct predictor. To examine this question, we turn to two of the largest studies comparing subjects over time using "hard" outcomes, the Framingham Offspring and MESA cohorts. They had low or high LDL-C, but universally high LDL-P. Conversely, look at the individuals with the highest event-free survival. They had high or low LDL-C, but universally low LDL-P." (Attia P. 2019)

"If you want to do the same exercise, but in reverse (i.e., look at the rate of events occurring rather than freedom from events), and do so in a much more heterogeneous population, look at the cumulative incidence of events in the Multi-Ethnic Study of Atherosclerosis (MESA) population. The exact same pattern emerges: high LDL-P (independent of LDL-C) predicts more events, while low LDL-P (independent of LDL-C) predicts fewer events. This point is not subtle and it's one of the few times when "eyeball statistics" do the trick-your eyeballs tell you the answer even if you don't know the difference between a Cox proportional hazard ratio, a Fisher's exact test, and a box of Lucky Charms." (Attia P. 2019)

"Cholesterol can only enter the arterial wall within apoB particles. However, the mass of cholesterol per apoB particle is variable. Therefore, the mass of cholesterol that will be deposited within the arterial wall is determined by the number of apoB particles that are trapped within the arterial wall. The number of apoB particles that enter the arterial wall is determined primarily by the number of apoB particles within the arterial lumen. However, once within the arterial wall, smaller cholesterol-depleted apoB particles have a greater tendency to be trapped than larger cholesterol-enriched apoB particles because they bind more avidly to the glycosaminoglycans within the subintimal space of the arterial wall. Thus, a cholesterol-enriched particle would deposit more cholesterol than a cholesterol-depleted apoB particle whereas more, smaller apoB particles that enter the arterial wall will be trapped than larger apoB particles. The net result is, with the exceptions of the abnormal chylomicron remnants in type III hyperlipoproteinemia and lipoprotein (a), all apoB particles are equally atherogenic." (Sniderman et. al. 2019)

What Dr. Attia and Dr. Sniderman have excellently surmised is that the data is clearly showing us that the LDL-particle number and apolipoprotein B particle number are the key biomarkers to track as of today. This is really important when you want to best assess your risk for needing a medicine post lifestyle management attempts. Unfortunately, this is not the current testing methodology for most primary care providers at this moment.

Therefore, in 2020, assuming we are using the correct test to assess risk, if we have an elevated LDL-p or apo-B level despite our best efforts to reduce risk, it is time to consider pharmaceutical drugs for event reduction. This is a very hard but important decision because this is a lifelong decision.

Knowing which drugs work in which phenotype of human disease is critical? Knowing how to speak to your provider about a drug's risk is critical because some are not well versed in the topic. For example, some statin class drugs cross the blood brain barrier more readily than others potentially increasing dementia risk. You need to understand relative risk. For example, a classic statin drug will protect 2-3 out of 7 people at risk over 10 years while the other 93 treated patients have no benefit and 4-5 still expire despite 10 years of therapy. These are the current statistics.

The drug treatment topic is crazy complicated in the era of pre-epigenetic risk understanding. Because of this reality, I will take my time in preparing a quality piece. What I will try and do sometime in the next few weeks or months is answer this question.

Next cardiology series piece: which drugs and why?

Dr. M

Sniderman JAMA Cardiology Article