Cholesterol, Statins, and PCSK9
Statins, a greater than $27 billion dollar per year cash cow for pharmaceutical companies, are nearing the end of their patents. So what can the drug companies come up with next to continue to cash in on the fat-phobia that has been so carefully planted and cultivated in our collective minds? The answer: PCSK9 Blockers. A drug currently under development, designed to get that dreaded cholesterol number even lower (and keep the money train climbing higher and higher).
A Background on Cholesterol
People (doctors included) have been trained to be terrified of cholesterol—the lower the better, right? Wait a second, though. Let's pause to ask some questions first. Just what the heck is cholesterol anyway, why do we have it, and why is it so life-threatening?
A brief jaunt over to Wikipedia can give us a great concise picture of what this substance is:
Cholesterol, from the Greek chole- (bile) and stereos (solid) followed by the chemical suffix -ol for an alcohol, is an organic chemical substance classified as a waxy steroid of fat. It is an essential structural component of mammalian cell membranes and is required to establish proper membrane permeability and fluidity. In addition, cholesterol is an important component for the manufacture of bile acids, steroid hormones, and vitamin D. Cholesterol is the principal sterol synthesized by animals;
Cholesterol is a vital component of the cell membrane of every cell of your body, and it is necessary for the formation of bile acids and hormones (vitamin D is a hormone). Cholesterol is so critically important to life that the vast majority of the cholesterol in your body is not gotten through diet, but is produced by the body itself.
That answers the what and why of cholesterol, but then, if it's so vital to life, why is it also so deadly? That, of course, begs the question: is it really deadly? The answer is decidedly no.
So where did the big stink come from? In the early days of cholesterol research it was found that hardening and clots in the arteries were comprised mainly of cholesterol. The simple logic is that if you remove cholesterol from your food, you prevent excess cholesterol from building up in your arteries. Thus was born the recommendation for a low-fat diet that continues to this day. Fortunately the science has continued on to discover that the processes of fat digestion, blood cholesterol level regulation, and atherosclerosis formation is far more complicated than that simplistic logic accounts for. Unfortunately for our now overweight, diabetic, heart-diseased, cancerous, hypertensive society, the recommendations for a low fat diet which got them into such a sad state is still being pushed on us as the gold standard of diets.
Cholesterol, being a non-water-soluable fatty substance, must be transported around our aqueous blood stream in a water-soluable package. What scientists didn't know (or, at least, couldn't measure) in the early days of the low-fat movement, was that these packages (called lipoproteins) come in various different sizes, and it is these different sizes that make a huge difference. Although not a cholesterol themselves, these lipoprotein transports are used to refer to the cholesterol they carry. Misleading, really, since it is the lipoproteins themselves that are the (potential) cause of problems and not necessarily the cholesterol.
The two primary groupings of these cholesterol transports are high density lipoprotein (HDL, this is the "good cholesterol") and low density lipoprotein (LDL, the "bad cholesterol"). One of the primary functions of HDL is to carry cholesterol back to the liver for recycling or disposal, whereas the function of LDL is to carry cholesterol from the liver to tissues that need it.
As it turns out, total cholesterol is a non-indicator for heart health risks. Let me restate that: total cholesterol tells you nothing about your cardiovascular risks. Right now the current recommendation is that total cholesterol be lower than 200 mg/dL. This number has no basis in any research. In fact, at the time the recommendation was put in place, the average cholesterol of an adult was somewhere in the 220-250 range—instant market!
What can, it turns out, tell you that you are at increasing risk for heart disease is a low ratio of HDL to total cholesterol, a low ratio of HDL to triglycerides (these are fats created by the liver, usually made out of carbohydrates, and shipped out into the blood), or the size of the LDL particles switching to pattern B. LDL particles can be large and "fluffy" or "bouyant" (pattern A—good), or they can be small, dense, and "sticky" (pattern B—bad).
Another worrisome fact is that low cholesterol is an indicator for increased risk of other diseases like cancer. For example, men with cholesterol below 190 are at 3 times the risk of colon cancer than men with levels greater than 220! Why do we want to get rid of cholesterol again?
So, what about statins? Statins are also known as HMG-CoA Reductase (HMGCR) inhibitors, because they inhibit HMGCR (naturally)... but what the heck is HMGCR?! HMGCR is an enzyme critical to an early stage of the mevalonate pathway (a series of chemical reactions in the body involving mevalonic acid). This pathway is responsible for producing not only cholesterol, but also dolichol and coenzyme-Q10, each of which also have important functions in the body.
NOTE: If you are taking a statin I urge you to consider getting off of it as soon as possible (and make sure you are talking to a doctor about it), but, if you absolutely won't stop taking it, please take a CO-Q10 supplement with it! Without CO-Q10 the body's muscles are unable to function and repair themselves properly which is why one of the side-effects of statins is muscle pain, weakness, and irreversable myopathy—including, ironically, heart muscle. You can, like my dad, end up with a severely weakened heart and a pace-maker—despite having no blockages in the arteries.
So, by inhibiting the pathway that leads to the synthesis of cholesterol, statins reduce the total cholesterol in the body. BUT WAIT! Remember that little tidbit of information about total cholesterol? That's right, total cholesterol is a non-indicator for atherogenic risk (atherogenesis: the formation of plaques in the arteries).
To decrease risk, one must increase the ratio of HDL to LDL (statins can't do that), increase the ratio of HDL to triglycerides (statins can't do that), and/or change LDL particle size to the healthier pattern A (statins can't do that, either). When you pore over the studies, you find that, really, only men aged 45-65 who have previously had a heart attack see a minimal benefit in preventing future heart attacks—and that comes with the increased risk for not just muscle problems (as stated earlier), but obesity, diabetes, and cognitive impairment. It is not an effective preventative measure for heart attacks (or stroke or mortality) in anyone. Not worth the trade off in my estimation.
On a side note, giving statins to teens and pre-teens, and idea that has seen serious discussion, would be a disasterously horrible idea. If you are just looking at cholesterol, then you might find high numbers in this age group, but let's not forget one of the other main functions of cholesterol: the production of steriod hormones, e.g., testosterone, estrogen, and progesterone. This means that the body is going to start synthesizing more cholesterol before and into puberty as it starts to ramp up the production of the necessary sex hormones. I'm sure the stunting of that process is not a desired outcome for anyone.
Proprotein convertase subtilisin/kexin type 9—now that's a mouthful! This is an enzyme that the body produces as part of LDL regulation. Cells have on their surface LDL Receptors (LDLR) that will bind with LDL particles and draw them into the cell. Once the LDL has been transported into the cell, the LDLR is recycled back to the outer membrane where it awaits the next LDL particle to begin the process all over. (LDLR is exceptionally prevalent in the liver where cholesterol recycling and disposal is regulated.)
What if the body wants to down-regulate the intake of LDL (especially in the liver)? This is where PCSK9 comes in. PCSK9 will bind to the LDLR before it transports an LDL particle into the cell. Once cellular transport has occurred, instead of getting recycled back to the cell membrane, the PCSK9-bound LDLR will remain in the endosome where it will be broken down. The result is that the cell in question has fewer inroads for the absorption of LDL.
By blocking this down-regulation of LDL intake, the PCSK9 Blocker insures that the liver continues full apace at its job of removing and recycling cholesterol. Even though the body may be desperately trying to signal your liver to slow this process down to conserve LDL in light of scarcity (as a result of a statin, for example), a PCSK9 Blocker will make sure that you continue to dump it out unincumbered by something as silly as the body's desperate need for repair and renewal. This is why research is showing that a statin plus a PCSK9 blocker is significantly better at lowering total cholesterol (which, as stated before, is worthless).
Can they be any good? Possibly. Some forms of familial hypercholesterolemia (genetically-caused, chronicly-high cholesterol) may be caused by a mutation of the gene which produces the PCSK9 enzyme which causes it to become hyperactive. In such cases, the body can't not tell the liver to stop disposing of LDL (have fun dissecting that sentence!). I can imagine how a PCSK9 Blocker would work much much better than a statin (not in addition to one) for the very rare set of individuals with this problem.
If Not Cholesterol, Then What Causes Atherosclerosis?
LDL and HDL are transports for cholesterol which is needed in every cell membrane you have. If a cell gets damaged, worn out, or needs to reproduce, it's going to need cholesterol. With that in mind, the formation of plaques is really a two-fold process.
First, damage is caused to the arterial wall. This is usually from high levels of carbohydrates in the blood which act as in inflammatory agent. To visualize this inflammation, imagine rubbing a firm brush on the same spot on your skin once every minute or so. Once or twice, and no big deal, but keep it up for a few hours or days, and you'll end up with a bloody arm. The body then, naturally, wants to send LDL particles to this site to initiate cellular repair.
Now, as if causing all this inflammation weren't bad enough, a diet high in carbohydrates will (amongst other things) change your LDL profile to pattern B (the bad one). So, to add insult to injury, the LDL particles coming to help repair the damage are small and "sticky" and get stuck in the artery wall where the build up and oxidize—causing more inflammation and more problems instead of helping.
The problem is not with the cholesterol, or even with the LDL particles, it's what is causing the inflammation in the first place setting off the whole chain reaction. Yep. Sugar, not fat, causes heart disease.
What is the best way to avoid this and other chronic illnesses like cancer, hypertension, stroke, diabetes, gout, and on and on? Don't get them in the first place! I know it kind of sounds silly to put it that way—I mean, who chooses to get a chronic disease? Consider, however, that their causes aren't mysteries, and, contrary to what has become accepted as normal, they aren't a natural part of aging that you just have to accept. They are a result of your body eventually being unable to keep up with the repairs of constant internal damage being done, primarily, through diet. If you eat right from the get-go—or as soon as you can—you greatly reduce your chances of getting one (or more) of these horrible diseases. If you already have one, eating right will work wonders in treating (and often curing) the problem.
This all can be visualized with a fun little analogy:
- Low-Fat Doctor: "During your recent exam we noticed you have many scabs forming all over your skin. This is a serious indicator of health risk. Please, take this drug that will inhibit the formation of scabs." (Patient eventually dies from hemorrhaging.)
- Low-Carb Doctor: "During your recent exam we noticed you have many scabs forming all over your skin. This is a serious indicator of health risk. Please, stop getting into knife fights." (Patient moves out of neighborhood and becomes successful water ballet teacher.)
This is Your Heart on Drugs...
Where might all this drug therapy end up? In the crapper would be my guess. As we continue to remove the body's ability to synthesize, use, and properly process one of the most fundamental substances of each and every one of its cells, I predict we will continue to see chronic disease rates and associated mortality continue to climb.
What effect will PCSK9 blockers have? I would bet that they do indeed reduce the amount of atherosclerosis in many people, but that we will see an even greater increase in cancer, diabetes, adhd, autism, schizophrenia, alzheimers, and who knows what else. These diseases have already seen exponential growth in a short time, with no indication that it's letting up soon.
Until we as individuals and as a society can get rid of this stupid phobia of fat and cholesterol and we stop underestimating the enormity of impact that diet has on our bodies (even when we're young), things are only going to get worse and worse—and big pharma is only going to get richer and richer off of our chronic illness and lazy desire for a magic pill to make it all go away.
But there is no magic pill; there is no shortcut. We've got to learn to eat better.