Can Further Lowering of Blood Cholesterol Save Lives?

For many years, lowering blood levels of low density lipoprotein cholesterol (LDL-C) has been a key target for individuals with cardiovascular disease (CVD) and healthy people at increased risk for developing such disease.

Alcohol and Heart Disease

Statin drugs play a key role for risk reduction and are prescribed to millions of people worldwide. Apart from lowering blood cholesterol, these drugs have a number of effects that are potentially beneficial. For example, their anti-inflammatory effect may be of importance.

The death rate from CVD has declined rapidly during the last few decades in most developed countries. Research indicates that this may partly be due to statin therapy. However, despite the widespread use of statin drugs, CVD still contributes importantly to morbidity and mortality around the world.

A new class of drugs, so-called PCSK-9 inhibitors, appears to significantly lower LDL-cholesterol among individuals not taking statins as well as those already on statin therapy. Many experts believe these drugs may be helpful for individuals who don’t tolerate statins as well as those not achieving target levels of LDL-C on statin therapy. The new PCSK9 inhibitors are so-called monoclonal antibodies which are developed by biologic methods. They can not be administered orally and are usually given by a subcutaneous injection with a two to four weeks interval.

Cholesterol and Atherosclerosis

Atherosclerosis is a form of chronic inflammation resulting from complex interactions between lipoproteins, white blood cells, different components of the immune system and the normal elements of the arterial wall. This process can lead to formations of atherosclerotic lesions or plaques that often protrude into the lumen of the artery causing vessel narrowing which may ultimately affect blood flow. If this occurs in the coronary arteries, it may cause damage to the heart muscle and induce serious irregularities of heart rhythm. Rupture of an atherosclerotic plaque may lead to thrombosis causing an acute occlusion of the artery resulting in heart attack.

There are many factors that contribute to atherosclerosis, one of which is elevated blood cholesterol. Although cholesterol is important for many bodily functions, elevated plasma levels appear to play an important role in the initiation and progression of atherosclerosis. In animal models, atherosclerosis will not occur in the absence of greatly elevated levels of plasma cholesterol. High levels of plasma cholesterol also appear to be an important contributor to atherosclerosis in humans, although the threshold level that must be exceeded to produce clinically relevant disease appears much lower than that in animal models, possibly because lesion formation occurs over many decades. Atherosclerotic clinical events are uncommon among people with lifelong very low plasma cholesterol levels. It must be emphasised however, that it is lipoprotein that interact with the arterial wall and initiate the cascade of events that leads to atherosclerosis. Cholesterol is only one of many components of lipoproteins.

The Role of LDL and the LDL-Receptor

A causative role for cholesterol in itself has never been proven, although it appears that atherosclerosis will not occur without it being present in the arterial wall. Measurements of total cholesterol only indirectly reflect the lipoproteins that transport the bulk of cholesterol and are the most atherogenic. In fact, measuring the number of LDL-particles (LDL-P) appear more predictive of risk than the measurements of the cholesterol mass within these particles (LDL-C).

When inside the arterial wall, LDL can undergo a variety of modifications including oxidation, uptake by white blood cells called macrophages, formation of so-called foam cells and the initiation of inflammation. This cascade of events may ultimately result in an atherosclerotic plaque within the vessel wall. Obviously, cholesterol is not the cause of all this, but it is always involved. So, is it true that atherosclerosis is more likely to occur if plasma concentration of LDL-cholesterol is high than if it is low. The answer is yes, and it is supported by a number of scientific studies.

The liver is the gatekeeper for LDL and is responsible for its clearance. Liver cells express LDL-receptors on their surface, that bind LDL and remove it from the blood stream. After binding to the LDL-receptor, the LDL/LDL-receptor complex is moved to endosomes within the liver cells, where the LDL is released from the complex. The LDL receptor then moves back to the cell surface where it can bind to additional LDL-particles. This circle leads to removal of LDL-particles from the circulation which can be measured as a reduction in LDL-cholesterol levels. The free LDL left within the cells is transported to lysosomes and degraded into lipids, free fatty acids and amino acids.

PCSK9

PCSK9 (Proprotein convertase subtilisin-like/kexin type 9) is a protein that regulates the expression of LDL-receptors in the liver. PCSK9 is produced by liver cells and released into the blood stream. PCSK9 binds to the LDL-receptor on the surface of liver cells, together with LDL. It moves into the cell, together with the LDL-receptor/LDL complex. After LDL is released from this complex, the LDL – receptor/PCSK9 complex is taken up by lysosomes for degradation, preventing the recycling of the LDL-receptor to the cell surface. Thus, PCSK9 is responsible for the degradation of LDL-receptors and therefore plays a critical role in the regulation of LDL-cholesterol levels.

Interestingly, mutations on the human PCSK gene expression that lead to a loss of PCSK9 function are found in 1 – 3 percent of the population. These mutations have been associated with lower LDL-C and a significantly lower incidence of coronary heart events. Inhibition of the interaction between PCSK9 and the LDL receptor may potentially lower LDL-C. A monoclonal antibody directed against PCSK9 could potentially lower LDL cholesterol if it blocks the interaction of PCSK9 with the LDL – receptor on the surface of liver cells. This may allow LDL- receptors to recycle to the cell surface, after releasing LDL within the cell, instead of being taken up and degraded in lysosomes. Increased concentration of LDL receptors on the surface of liver cells may lead to increased clearance of LDL, which will be reflected as reduced levels of LDL-cholesterol.

PCSK-9 Inhibitors – Are They the New Wonder Drugs?

Whatever we think of cholesterol we have to keep an open mind about the new PCSK-9 inhibitors. There are large ongoing randomized clinical trials testing whether these drugs will prolong life and reduce the risk of future cardiovascular events among individuals with CVD. The results of these studies are eagerly awaited. The  may provide answers to a lot of unresolved questions regarding the lipid hypothesis.

Some of the popular “internet doctors” have slammed the PCSK9 inhibitors before they are scientifically tested. Many of them believe that lowering cholesterol is always harmful and that statins drugs are always bad. Of course, if you believe so, you won’t like the idea of PCSK-9 inhibition. But remember, don’t let cognitive dissonance steer your thought processes.

I’ve written a lot about statin drugs on my blog and I worry that they are prescribed to millions of individuals who don’t need them. I also fear that adverse effects of statins are underreported. However, statins are very important drugs for many patients and they are unfortunately often not prescribed when they should be. The world is not black and white and neither is the art and practice of medicine.

Apart from lowering LDL-cholesterol, the new PCSK-9 inhibitors also lower blood levels of non-HDL cholesterol, triglycerides, apolipoprotein B and lipoprotein(a). However, it is important to keep in mind that a change in these biomarkers induced by therapy does not always incur clinical benefit. Ezetimibe, a potent inhibitor of intestinal cholesterol absorption, has been shown to be safe, tolerable and effective at lowering LDL-C, non-HDL cholesterol andapolipoprotein B, each of which has been correlated with improved clinical outcomes, alone or in combination with a statin. However, randomized clinical rials have shown mixed results and with a few rare exceptions, the use of the ezetimibe is not recommended for cardiovascular risk prevention.

Whether treatment with PCSK9 inhibitors will positively influence the atherosclerotic process and reduce risk among individuals with CVD remains to be seen. It is also important to learn if there is any collateral damage. We will not know the answer to these questions unless they are tested by scientific methods. Until then, I won’t believe anyone who pretends to know the answer.

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charles grashow
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charles grashow

The money quote from the good doctor

“In animal models, atherosclerosis will not occur in the absence of greatly elevated levels of plasma cholesterol. High levels of plasma cholesterol also appear to be an important contributor to atherosclerosis in humans, although the threshold level that must be exceeded to produce clinically relevant disease appears much lower than that in animal models, possibly because lesion formation occurs over many decades.

Atherosclerotic clinical events are uncommon among people with lifelong very low plasma cholesterol levels.”

aelephant
Guest

Dr. Mercola is incorrect as early as the 2nd paragraph:

“In order to obtain the incredibly low LDL levels now recommended, you typically have to take a cholesterol-lowering statin drug, and sometimes two or three of them in combination.”

I’ve never heard of people taking more than one statin drug. They might switch you from a less potent one to a more potent one or vice versa, but it would be nonsensical to use them in combination.

Axel F Sigurdsson
Admin
Axel F Sigurdsson

@ aelephant

You’re absolutely right. Here‘s the link if someone wants to read Dr. Mercola’s article.

Richard S.
Guest
Richard S.

Thank you. A thoughtful and well-reasoned approach.

What do you think of calcium testing? Reading lipid panels these days seems so indirect, and with them we’re left trying to guess the odds of bad outcomes. I’ve read that calcium tests can tell us whether our arteries have plaque build-up or not, and how much. For those at risk, that would seem to be a more logical and direct approach, to determine whether they really are at risk, or not.

I’d like to hear your thoughts on that. Thanks!

Axel F Sigurdsson
Admin
Axel F Sigurdsson

@Richard S.
That’s a highly relevant question Richard. Coronary artery calcification (CAC) assessed by computerized tomography (CT scan) is a very strong predictor of future risk. For a variety of reasons including expense and radiation exposure concerns, routine CAC testing is not currently advocated. Whether CAC outperforms parameters lipid or lipoprotein testing such as LDL-C, Non HDL-C, LDL particle number (LDL-P) or Apolipoprotein B is still debated. Here is a very nice overview on the CAC, lipids and lipoproteins if you are interested. You may have to register fore Lecture-pad but I think everyone can do that, and it’s free.

JeffryGerberMD
Guest

Another great balanced post Axel. PCSK9 inhibitors increase the clearance of LDL-C (and its surrogates) and Ezetimibe decrease absorption. Net effect is the same to lower blood cholesterol, yet Ezetmibe has not been shown to reduce CV risk. It will be interesting to see if the PCSk9 reduces risk or not.

I would love to see research looking at new therapies directly addressing the inflammatory component of atherosclerosis and CV disease. For instance therapies targeting the CV immune response, superoxide, etc.. Do you know of any research?

Axel F Sigurdsson
Admin
Axel F Sigurdsson

Jeff. There is an ongoing randomized placebo controlled trial, called The CANTOS trial testing the efficacy of Canakinumab in patients with a history of myocardial infarction (MI) and raised levels of hsCRP suggesting chronic low grade inlfammation. Canakinumab is a fully human antihuman IL-1 beta antibody. It is administered by a subcutaneous injection every three months. Canakinumab is expected to reduce the risk of future occurence of major cardiovascular events in patients with past MI by preventing IL-1 beta mediated vascular wall inflammation. Ten thousand patients have been randomized in the trial. There is also an ongoing study with methotrexate… Read more »

Mie
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Mie

Jeff

“Net effect is the same to lower blood cholesterol, yet Ezetmibe has not been shown to reduce CV risk.”

Isn’t this at least partially because ezetimibe has – mainly – been compared to other medication (e.g. niacin) and examined in study populations already on statins & with quite good lipid levels? Of course you need to compare any new potential treatment to the best existing option, but the outcome of that doesn’t necessarily mean that the drug per se doesn’t work. E.g. people who don’t tolerate statins may benefit from taking ezetimibe as these people benefit from LDL lowering.

Axel F Sigurdsson
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Axel F Sigurdsson

@Mie
Despite lowering LDL-cholesterol, Ezetimibe alone or in the presence of statins has not been shown to have any irrefutable beneficial effects on atherosclerosis or cardiovascular morbidity and mortality. Studies have shown that statins are much more effective than Ezetimibe when it comes to atherosclerois regression as well as clinical end-points. That may be due to the fact that statins lower LDL-cholesterol (or LDL-particle number, independent of cholesterol mass) more than Ezetimibe, or because statins partly (or mainly, if you prefer) work through other mechanisms (anti-inflammatory, vasodilatory, antithrombotic).

RichardOrnishForLife
Guest
RichardOrnishForLife

Axel, one the few reads from you that I actually like and find useful. As for Ezetimibe, a top-snotch lipid expert Evan Stein shares his views here: https://www.youtube.com/watch?v=b1PSWVRB0fY As for saying that it has not been proved that cholesterol is the causal agent in influencing CHD, that’s like saying that the theory of evolution has never been proved. Are there actually any other people apart from the mathematicians that can prove something, is science even about proving something in the end? Scientists work with hypothesis. However, I think its rather compelling evidence for the lipid theory that that once an… Read more »

RichardOrnishForLife
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RichardOrnishForLife

Axel, what studies do you have in mind? In ENHANCE -trial Ezetemibe was administered on a group of well-treated FH patients. As Evan Stein basically concluded, LDL reduction has shown to yield decreased risk of CHD independent of the mechanism used, everything seems to work: hormone therapy (although this carry some serious side effects), bile-acid sequestrants, bypass of the illeal, diet (Ornish, Morrison, Pritikin, Esselstyn, etc) and genes (so far at least the effect of 9 different LDL lowering polymorphism have been studied including a gene that lower cholesterol via HMG-CoA). Why would Ezetemibe not work when given a chance?… Read more »

Mie
Guest
Mie

Axel, What are the trials which have studied the efficacy of ezetimibe treament vs plasebo, without prior/ongoing statin treament? Could you name a few? I can’t think of any studies in which ezetimibe would’ve been studied in e.g. 4S setting, that is, among CVD patients who can be expected to benefit the most. In addition, yes, statins do lower LDL more efficiently than ezetimibe. Which is precisely why they work. The pleiotropic effects of statins are more like icing on the cake, as the statins which lower LDL the most have consequently been proven to be the most efficient drugs… Read more »

Axel F Sigurdsson
Admin
Axel F Sigurdsson

@Mie
I’m not aware of any studies that have assessed the efficacy of ezetimibe in patiens with CVD not taking statins. It world be unethical not to give statins in this situation unless those are statin intolerant patiens. Ezetimibe added to statin therapy further lowers LDL-C compared with statins alone, but plaque volume is not reduced (ENHANCE)and this is not translated intolerant fewer cardiac events.

JeffryGerberMD
Guest

Mia, yes to what Axel said above about other mechanisms. I was comparing the net effect of Ezetimibe to PCSK9 inhibitors to suggest that if these medications only work by lowering blood cholesterol concentration and have no other mechanisms of action, perhaps that is why they might NOT reduce cardiovascular risk. There is still much to learn about PCSK9 inhibitors.

RichardOrnishForLife
Guest
RichardOrnishForLife

Mi(k)e has it goin’, I agree, well done, Mie. I like that we can agree at least 1% of the time. It’s hard to make a point against the LDL theory by concluding that Ezetemibe doesn’t reduce the amount of plaque in arteries of well-treated FH patients (who as a consequence already have rather low LDL). And, as my medpage -today youtube source revealed, there are atherosclerosis experts out there who claim that ezetimibe has unwanted properties that potentially jeopardize any benefits that are gained by LDL lowering. I cannot judge whether this is correct or not, but at least… Read more »

RichardOrnishForLife
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RichardOrnishForLife

BTW,

Medpage today did a 3-piece short-clip of the whole ezetimibe debate: I already posted the first part, but here’s 2 & 3. Good material.
https://www.youtube.com/watch?v=cGQULIePcEg
https://www.youtube.com/watch?v=wFRiEPjlkfY

Mie
Guest
Mie

Axel, “I’m not aware of any studies that have assessed the efficacy of ezetimibe in patiens with CVD not taking statins. It world be unethical not to give statins in this situation unless those are statin intolerant patiens.” Well then, there you go. Precisely my point. What this means is that there’s no need to favour ezetimibe therapy in people who tolerate statins. What this doesn’t mean is that ezetimibe doesn’t work and/or that it shouldn’t be used in patients who need to lower their LDL levels but cannot handle statins. “Ezetimibe added to statin therapy further lowers LDL-C compared… Read more »

charles grashow
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charles grashow

@ROFL

“Chimpanzees don’t eat meat; they eat very little fat. They have LDL levels in the range of 40 to 70, and they don’t get atherosclerosis. Maybe we wouldn’t get atherosclerosis either if we had levels this low.”

I eat meat, full fat diary AND I take 10mgs Atorvastatin/day + other targeted supplements an my last blood work (2/24/14) shows LDL of 47!

RichardOrnishForLife
Guest
RichardOrnishForLife

Doc,

for “natural” and effective LDL-lowering therapy, check out some of these dishes at Forks Over Knives website. This stuff looks absolutely delicious. And, it’s very cheap to pull it off, very affordable foods. Who would not eat this?
https://www.forksoverknives.com/mexican-rice-soup/

charles grashow
Guest
charles grashow

@ROFL

Regardless – why would it matter how my LDL of 47 was achieved? That’s way lower than Dr. Esselstyn achieved with his patients and they were on a very low fat diet + statins!

My food is affordable – raw goat milk, kefir, grass fed beef purchased at the farm.

RichardOrnishForLife
Guest
RichardOrnishForLife

Charles, I don’t know whether it matters or not, probably not. But there are other chronic diseases that have been connected with the intake of animal foods. Although, in many of these diseases LDL cholesterol seem to play out a pivotal role (prostate cancer progression, Alzheimer, etc). Moreover, Esselstyns and Ornish patients seem to enjoy immunity from atherosclerotic events even with sub-optimal LDL numbers. Nevertheless, drinking raw goat milk seems like a very stupid idea already from a sheer food hygiene perspective. Esselstyn’s own colleague at the Cleveland heart clinic achieved much lower LDL that you did, and without statins.… Read more »

charles grashow
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charles grashow

https://www.sciencebasedmedicine.org/bill-and-hillary-clinton-go-woo-with-mark-hyman-and-functional-medicine/#more-31090

One of the first things Dr. Hyman did was to wean Mr. Clinton off his previously prescribed vegan diet. Despite persistent news media reports that he is vegan, Mr. Clinton does occasionally eat fish and lean protein. “It’s hard being a vegan to eat enough good, quality protein and not have too much starch,” Dr. Hyman said over lunch at the Four Seasons restaurant in New York. “I know a lot of fat vegans.”

charles grashow
Guest
charles grashow

@ROFL “drinking raw goat milk seems like a very stupid idea already from a sheer food hygiene perspective” Do a Google search and see how many people die from food poisoning from veggies as to the number who die from drinking raw milk. As to the safety – sine my wife and I live in NY https://www.agriculture.ny.gov/DI/DIFAQ.html To sell raw cow milk directly from the farm to consumers, a producer is required to obtain a Raw Milk Sales Part 2 permit. Even if the farmer gives away one gallon of milk, a permit is required. To receive a permit the… Read more »

RichardOrnishForLife
Guest
RichardOrnishForLife

In regards to the Clinton’s fair, yes, Clinton no longer takes advice from a cardiologist, professor and a highly acclaimed clinical researcher, Dr. Dean Ornish whose studies have been published in some of the most prestigious scientific journals and whose program is covered by the Medicare, instead he seem to listen GP who likes functional medicine whose program is not covered by Medicare (this is our and Clinton’s loss): Dr. Hyman carries packets of macadamia nut, walnut or coconut butter in his jacket pocket, and he advises busy patients like Mrs. Clinton to do the same. Grass-fed beef and turkey… Read more »

RichardOrnishForLife
Guest
RichardOrnishForLife

“Do a Google search and see how many people die from food poisoning from veggies as to the number who die from drinking raw milk”. That’s like saying that scuba diving carries absolute no risks because people die more often in car accidents. Most Americans eat at least some vegetables every day, whereas pretty only the Western Price Foundation people a drink raw milk, that’s like what, 0,001% of the US population? As I said, you don’t come out as a very rational thinker, but at least you doing something right, taking 10mgs of atorvastatin daily, that is. Raw milk… Read more »

charles grashow
Guest
charles grashow

@ROFL

Again I ask – if my current TC is 100, LDL is 47, HDL is 44, Triglycerides are 43 then HOW I go to those levels should be irrelevant – correct?

FrankG
Guest
FrankG

“Chimpanzees don’t eat meat; they eat very little fat. They have LDL levels in the range of 40 to 70, and they don’t get atherosclerosis. Maybe we wouldn’t get atherosclerosis either if we had levels this low.” Maybe..? He doesn’t seem to share your absolute faith ROFL.. he must be an heretic 😛 As for Chimpanzees not eating meat: as ever, you are playing fast and loose with the truth… Chimps Hunting Monkeys http://www.youtube.com/watch?v=mpYViR9MqrU Chimpanzees team up to attack a monkey in the wild – BBC wildlife https://www.youtube.com/watch?v=A1WBs74W4ik Spear-Wielding Chimps Studied https://www.youtube.com/watch?v=FyGxQq7jSA8 https://www.allaboutwildlife.com/what-do-chimps-eat “Unlike other apes such as gorillas and… Read more »

charles grashow
Guest
charles grashow

@Frank G

Remember – according to ROTF I’m not a rational thinker – maybe you’re not one either?? If so welcome to the club!

RichardOrnishForLife
Guest
RichardOrnishForLife

Frank, you are so fervently interested in proving me wrong that you loose every drop of logical consistency. I am not bending the truth, I quoted John LaRosa, who told to the press that chimps eat very little fat, you took this as straw man and insisted that I claim that chimps eat no animal fat at all. I am very aware of the fact that chimps are highly opportunistic omnivorous. I also know that it has been shown that when diets rich in cholesterol and saturated fat are fed to monkeys of the genus Macaca, including the rhesus monkey… Read more »

FrankG
Guest
FrankG

@ROFL… on the contrary, I have little need to prove you wrong, as you do such a fine job of contradicting yourself at every turn.

I was well aware that you were quoting LaRosa… in fact I used the portion that you bolded “Chimpanzees don’t eat meat…” which is clearly baloney… so either he is an idiot, or you are an idiot for quoting him in support of your position.

Stop banging your own head against the wall… you cannot possibly think that you have any credibility here?

charles grashow
Guest
charles grashow

@ROFL

Again I ask – if my current TC is 100, LDL is 47, HDL is 44, Triglycerides are 43 then HOW I go to those levels should be irrelevant – correct? Or do I have to it a certain way for it to count?

charles grashow
Guest
charles grashow

@ROFL https://www.medscape.com/viewarticle/750954 “He (LaRosa) noted that levels of LDL below 70 are on a par with those of nonhuman primates who don’t develop atherosclerosis, adding that, like these primates, humans were designed to be vegetarians. “Our dental anatomy suggests that we are not meant to be meat eaters. Animals that eat meat have sharp tearing teeth, while we have flatter teeth more similar to vegetarian animals. I believe humans are not anatomically or metabolically designed to be meat eaters.” This is so pathetically stupid on so many levels it’s pathetic. If humans were designed to be vegetarian how come there… Read more »

RichardOrnishForLife
Guest
RichardOrnishForLife

Frank, for somehow Charles managed to come up with the bullet-proof money quote from Doc’s article, see the first comment on this text. You again could not grasp the take home message of LaRosa’s postulation. Thus, let me help you. John LaRosa’s point was that LDL levels under 70s are physiologically normal (lower the better), and that the closest relatives to humans have very low LDLs as a result for eating “very little fat”. Avoiding artery clogging saturated fats is a no-brainer given the whole Darwinian foundation of our biomedical research paradigm. Charles, take it easy, I am sure you… Read more »

FrankG
Guest
FrankG

@ROFL.. again, on the contrary it seems that you are the one in need of help and clarification… If you really think that folks here will accept “science”, or even medical advice from someone (or a person who quotes them) who evidently gets his knowledge of the natural world from Disney Studios, then you’re every bit as much of an idiot as I suggested above. “…and that the closest relatives to humans have very low LDLs as a result for eating “very little fat”.” Do you really need to be reminded that correlation does not show causation? Yes Chimpanzees may… Read more »

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