“Is my cholesterol too high?” may become an irrelevant question.

There was a time when the total cholesterol number rising above 240 meant that you had a simple condition called “high cholesterol” and that avoiding fat and perhaps taking medication could reduce your “cholesterol” level the blood. If you did this, you could avoid a heart attack. Cholesterol was described as a fatty molecule that clogged arteries in the heart and having too much of it made heart attacks and strokes more likely. This "plumbing" analogy made sense to almost everyone, so we proceeded to eat low fat diets and started taking Lipitor.
Did it help?

Not as much as you might think. Lipitor and other “statin” drugs are life-saving if you’ve had a heart attack, but the data on prevention are less impressive. One of the reasons is that it isn't simply a question of lowering cholesterol (and statins have other actions aside from cholesterol lowering).

Cholesterol isn’t just one thing. It’s many. Some forms help us, some forms can hurt us. Some come from our diet, many more are produced by our own body. In the absolute most basic discussion between physician and patient regarding cholesterol, the following points need to be made clear:

·        Total cholesterol is the sum of helpful molecules and harmful molecules
·        The breakdown of the “good” and the “bad” tells you more than the total
·        HDL is “good”
·        LDL is “bad”
·        Neither of them are actually “cholesterol”
·        They carry cholesterol
·        You want HDL to be high, because it is taking cholesterol back to the liver
·        You want LDL to be low, because it's dumping cholesterol out into the body
·        LDL is lowered by medicines
·        HDL is raised by exercise and eating “good fat” like olive oil
·        There are many other particles
·        And we don't know what they do

I’m not kidding, that is the most basic discussion that should occur. Does it even scratch the surface of the real complexity underlying the lipids in our blood? Not at all, says a November, 2011 study. In “The Human Plasma Lipidome.” (Free full article here) Drs Quehenberger and Dennis show us that the idea of good cholesterol and bad cholesterol is a ludicrously over-simplified description of the current understanding of lipids in our blood. In this paper, they identify almost 600 lipid molecule species in human plasma and reference other papers that assess true number of distinct molecules to be more on the order of hundreds of thousands. Let’s stop and think about what we are talking about here: not lipoproteins, or lipid particles in the blood, but actual molecules. These are things like cholesterol, arachidonic acid, triglyceride, that get carried in HDL, LDL and other particles that are measured in the lab. The sheer diversity makes the discussion of simple “lipid lowering” extremely complex.

These 600 or so types of lipid molecules aren’t the result of us eating eggs, or any other food, they are produced by the body for reasons that are very poorly understood. We know that having some amount of cholesterol is essential for health, but of those 600 newly described molecules, very few have an understood job to do in the body. "Cholesterol" itself is actually a group of molecules with various functions, some having to do with the cell walls and some having to do with signaling and inflammation in the body. In this lipid classification study, the researchers identified 22 variants of the cholesterol molecule which get manufactured in the liver and other tissues. To add to the confusion, the cholesterol family of molecules (whose function we don’t fully understand) represents less than half of the fatty molecules we can find in the blood. So, to recast the idea of lipids in the blood, the researchers in this field are referring to this as a “lipidome” as an analogy to the human genome. It’s a powerful term and different enough from our current descriptions that it should change the “should I take Lipitor?” question forever.

Most doctors understand that the question “is my cholesterol too high?” is not the right question to be discussing, but until recently, they didn’t have a means of expressing why to their patients (except for the very limited ideas of “good” and “bad” cholesterol). With the concept of a lipidome, that discussion could now take a different shape. Something like this:

“Is my cholesterol too high?”

“Well, that’s a more complicated question than you might think”

“Yawn”

“Stick with me here. There is not just one cholesterol, but many. There are 22 known types of cholesterol, and that LDL measurement is just a proxy for how much is in the body and where it might be going. Cholesterol does many things in the body and we aren’t sure what all of them are. Not only that, but the other things we call “lipids” in the body have at least 600 different forms as well. We’re pretty sure that the risk of heart attack and stroke is more related to balance and interaction of these molecules than it is about any absolute number. Just focusing on cholesterol, or LDL cholesterol, is probably way too simplistic. We aren’t even sure that drugs like Lipitor help us because they lower LDL. They are likely affecting some of the interactions between cholesterol and the lipid molecules that control inflammation in the blood vessels. Most of those plumbing graphics, showing clogged arteries that you see on the commercials, are misrepresenting how heart attacks happen. We used to think of it that way in the 80s, but we know way more about this stuff now.”

What this means for  patient care remains to be seen. But it seems likely that we will be measuring very different parameters than our current cholesterol panel in the near future, to distinguish which patients might benefit from treatment.

Meanwhile, there is a whole new class of lipid lowering drugs called "PCSK9 inhibitors," (These guys need a shorthand badly, I'm thinking perhaps, "PESKY 9"?) which were approved last summer by the FDA, that can lower LDL cholesterol to very low levels. So far, the drugs are outrageously expensive and only approved for people with genetic defects giving them triple high LDL levels . . . but all that will likely change over time, just like it did with statins. The new medicines will spread from those who truly need it, to those who might benefit, to those who have heard about it and demand it from their well-intentioned physician.




Since the new drugs are working on the old "plumbing" model of trying to "lower" "cholesterol," I think these drugs are a couple decades late to the cholesterol treatment party. But doctors really like the idea of lowering cholesterol, so there is a good chance these drugs will gain popularity as studies come back showing that they reduce heart attacks from "rarely" to "1/2 of rarely."

Newer drugs that take advantage of the emerging complexity of cholesterol science, rather than simply lowering bad cholesterol, will likely arrive in a decade. For now: let's all quit smoking and go for a walk --I'm pretty sure those two things will never go out of fashion for preventing heart attacks.
Having read this far, you might be interested in checking out my awesome book on Amazon:
What Is Fat For?


Reference:
The Human Plasma Lipidome
Quehenberger and Dennis
New England Journal of Medicine. November 10, 2011