Reducing LDL Cholesterol is the Wrong Target for Cardiovascular Disease

When people say "cardiovascular disease" in the context of blood cholesterol, they mean atherosclerosis. This is the name given to the build up of fatty deposits that narrow and weaken blood vessels, leading to heart failure and ultimately some form of disabling or fatal rupture - a stroke or heart attack. The primary approach to treatment is the use of lifestyle choices and drugs such as statins to lower cholesterol carried by LDL particles in the blood. Unfortunately, the evidence strongly suggests that this is the wrong approach, in that the benefits are small and unreliable.

Atherosclerosis does occur more readily with very high levels of LDL cholesterol, as illustrated by the early onset of the condition in patients with genetic disorders such as homozygous familial hypercholesterolemia, in which blood cholesterol can be as high as ten times normal. Yet reducing LDL cholesterol levels, even to as much as ten times lower than normal, does very little for patients with established atherosclerotic lesions. One has to look at the mechanisms of the disease in more detail to (a) see why this is the case, and (b) identify which classes of therapy should be attempted instead.

Atherosclerosis is essentially a consequence of the failure of a process called reverse cholesterol transport. When cholesterol becomes stuck in excessive amounts in blood vessel walls, macrophage cells of the innate immune system are called to the site. The macrophages ingest cholesterol and then hand it off to HDL particles. The HDL cholesterol is then carried to the liver to be excreted. This all works just fine in young people. Older people, however, exhibit growing levels of oxidized cholesterols such as the toxic 7-ketocholesterol. Even small amounts of these oxidized cholesterols disrupt macrophage function in ways that are otherwise only achievable through very sizable amounts of cholesterol. The macrophages become inflammatory, cease their work, become loaded down with cholesterol, and die. An atherosclerotic lesion is essentially a self-sustaining macrophage graveyard that will keep pulling in and destroying ever more cells, growing larger as it does so.

The right point of intervention in atherosclerosis is therefore macrophage function. Make macrophages resistant to oxidative cholesterol and cholesterol overload, as Repair Biotechnologies is doing. Or remove oxidized cholesterols from the body, as Underdog Pharmaceuticals is doing. The crucial goal is to allow macrophages to operate normally in the toxic environment of the atherosclerotic lesion; given enough time, it is in principle possible for these cells to dismantle even advanced and sizable lesions. That they do not normally do this is because of oxidized cholesterols or sheer amount of cholesterol, not any other inherent limit.

Doubt cast on wisdom of targeting 'bad' cholesterol to curb heart disease risk

Setting targets for 'bad' (LDL) cholesterol levels to ward off heart disease and death in those at risk might seem intuitive, but decades of research have failed to show any consistent benefit for this approach, reveals a new analysis. If anything, it is failing to identify many of those at high risk while most likely including those at low risk, who don't need treatment, say the researchers, who call into question the validity of this strategy.

Cholesterol-lowering drugs are now prescribed to millions of people around the world in line with clinical guidelines. Those with poor cardiovascular health; those with LDL cholesterol levels of 190 mg/dl or higher; adults with diabetes; and those whose estimated risk is 7.5% or more over the next 10 years, based on various contributory factors, such as age and family history, are all considered to be at moderate to high risk of future cardiovascular disease. But although lowering LDL cholesterol is an established part of preventive treatment, and backed up by a substantial body of evidence, the approach has never been properly validated, say the researchers.

Hit or miss: the new cholesterol targets

This analysis highlights the discordance between a well-researched clinical guideline written by experts and empirical evidence gleaned from dozens of clinical trials of cholesterol reduction. It further underscores the ongoing debate about lowering cholesterol in general and the use of statins in particular. In this analysis over three-quarters of the cholesterol lowering trials reported no mortality benefit and nearly half reported no cardiovascular benefit at all.

The widely held theory that there is a linear relationship between the degree of LDL-C reduction and the degree of cardiovascular risk reduction is undermined by the fact that some randomized controlled trials with very modest reductions of LDL-C reported cardiovascular benefits while others with much greater degrees of LDL-C reduction did not. This lack of exposure-response relationship suggests there is no correlation between the percent reduction in LDL-C and the absolute risk reduction in cardiovascular events.

Moreover, consider that the Minnesota Coronary Experiment, a 4-year long randomized controlled trial of a low-fat diet involving 9423 subjects, actually reported an increase in mortality and cardiovascular events despite a 13% reduction in total cholesterol. What is clear is the lack of clarity of these issues. In most fields of science the existence of contradictory evidence usually leads to a paradigm shift or modification of the theory in question, but in this case the contradictory evidence has been largely ignored simply because it doesn't fit the prevailing paradigm.

Comments

Hi there! Just a 2 cents.

I can respect that (because I'm alive and a survivor of it), but there is so much conflictual studies about atherosclerosis/LDL...
The big elephant in the room with 'lowering LDL' is that there is a thing as too low and not getting the big picture; which is making sure to take into account of the HDL levels; thus, the LDL:HDL ratio. You can't just reduce LDL, you must increase HDL - at the same time; not only reduce LDL and have insufficient HDL.

''The study was done as part of the Emory Cardiovascular Biobank. On average, the participants were 63 years old and about one-third were women. Their HDL levels ranged from a low of less than 30 mg/dL to a high of greater than 60 mg/dL of blood.

Over the course of the study, 13 percent of the patients had a heart attack or died from a cardiovascular cause.

At the study's end, the researchers concluded that patients with HDL levels in the middle-range of the spectrum -- meaning between 41 to 60 mg/dL of blood -- fared the best, having the lowest risk for heart attack or death from heart disease.''

You read right...patients with very high HDL died...not LDL...so you can have excess HDL - Too...I used to think you can go sky-high with HDL...but you can't. It is called a U-shape/
bell (shape) curve graph...for both HDL and LDL; there is 'balance'; which is that 41-60 mg/dL 'range/window' blood HDL. Under That = Bad; Over That = Bad. Thus, not Too Much, not Too Little; for both cholesterols. Studies saw that ultra-low LDL (alone) could be harmful too; you need it low (enough) and the HDL high (enough) too. We need Both cholesterols for function; but with age too much LDL and not enough HDL; in certain people they have ultra-high HDL levels (over 60mg/dL) and that is dangerous/will become fatal too. Most likely, it ends up the same as LDL, in reverse, and you get atherosclerosis despite very high HDL.

HDL is crucial to mop up the LDL and to control macrophage behavior; for it stops macrophage invasive behavior and changes it towards non-invasive; and stops it from LDL consumption. HDL can then do its job. But too much HDL, too much LDL, too little HDL, too little LDL -> atherosclerosis. This means we must strike 'the gold mean' which just enough HDL:LDL. They say in the study that people in the correct lower 'mid-range' window were the healthiest and least mortality. It means a mid-balance for function. That is why statin LDL lowering supplements are good but too much of them can alter LDL/HDL; with just too much HDL and too little LDL... this means we have to Carefully check our levels to 'fit in that range/window'...as we use statins or other cholesterol lowering drugs; so that we are sure there is Enough LDL reduction (to stop and reverse atherosclerosis) and that is a rise of HDL; but that we do not see extinction of LDL (no more/too low); nor do we see (an increase) above 60mg/dL of HDL; at that point if we did we would have to stop taking cholesterol lowering drugs (that reduce LDL and cause HDL increase) to restore 'a middle' cholesterol range that gives the best health. Because atherosclerosis will happen 'in reverse' when too high HDL and too little LDL.

Just a 2 cents.

Posted by: CANanonymity at August 12th, 2020 3:49 PM

Yikes.

The authors themselves are overstating the problem here (de Lorgeril is a long-time if moderate and not completely crazy LDL-C skeptic), the press release exaggerates the firmness and extent of their findings, and your opening paragraphs make the framing even worse, Reason.

They're not far off of reasonable if short-termist conclusions when they say "The negative results of numerous cholesterol lowering randomised controlled trials call into question the validity of using low density lipoprotein cholesterol as a surrogate target for the prevention of cardiovascular disease," in the sense that if you go just on trial evidence and a modest amount of pharmacoepidemiology and other observational data, assigning people who are otherwise low-risk to LDL-C-lowering therapy (like a statin) based just on elevated LDL-C does not seem to lower risk of events to any meaningful degree and has no effect on total mortality. This is why, controversially, the AHA/ACC guidelines a few years ago counciled physicians to stop doing that, in favor of giving people LDL-C-lowering therapy based on their overall risk score, irrespective of LDL-C level - ie, some patients should get it even if they have low LDL-C, and others should not get it even if they have high LDL-C.

However, this is quite different from saying that LDL-C is simply the wrong target for drug therapy: this is clearly shown by a meta-analysis of statin and nonstatin interventions to lower LDL-C (showing that it's the LDL-C lowering, and not the pleiotropic effects of statins per se, that does the trick); by a meta-analysis of trials featuring lowering LDL-C to levels well below existing targets; and by Mendelian randomization of genetic variants that lower LDL-C (again showing that it's not the non-LDL-C-lowering mechanisms of statins that lower risk). See the consensus statement from the European Atherosclerosis Society Consensus Panel that low-density lipoproteins cause atherosclerotic cardiovascular disease for more evidence.

The reason that strong effects on CVD events are not observed when targeting LDL-C levels alone is because (a) LDL particles are necessary causes of atherosclerotic disease, but not sufficient over the short term, and more importantly (b) the trials are too short-term, and you need the integral of time, since cardiovascular disease is a disease of aging driven by LDL particles.

Hence the call for "Eradicating the Burden of Atherosclerotic Cardiovascular Disease by Lowering Apolipoprotein B Lipoproteins Earlier in Life."

None of this is to take away, of course, from the fact that no degree of messing with LDL particle levels or other metabolic co-conspirators can truly do the job, and the need for damage-repair-based rejuvenation biotechnology such as direct rehabilitation or removal of of foam cells.

Posted by: Michael at August 12th, 2020 5:57 PM

May I suggest oxidized cholesterol is caused by high blood glucose?

Posted by: Bill at August 12th, 2020 8:29 PM

PS: Hi Bill! Just a 2 cents. Solid question, in my POV, and from what I lived (since I got/have this atherosclerosis disease for rest of life, I'll probably live less long due to this; it's why I turned vegetarian, removed junk food, removed cholesterol rich animal foods/fatty saturated fats foods or else I would be dead of it); that is why I am alive and survived blood clot embolism in large pulmonary blood artery. At 35 years old and weigthing 150lbs, 5'10''. Now 5 years later (I'm 40) and I'm still here.

I would say oxidized cholesterol formation is definitely accelerated by high glucose; since hyperglycemia causes glycation/glycoxidation of the proteins/molecules....and I noticed that very high carb load - causes arterial vasoconstriction, hardening, tightening, thus less blood flow...this can cause elevated blood pressure too in thinning/constricting/tightening vessels (both diabetes and high blood pressure are accelerated forms of aging; this was shown in epigenetic level; they demethylate faster and thus, telomere loss will accelerate under high glucose/glycation/glycoxidation/AGEs -> high IGF/insulin production/hyperinsulinemia -> mTOR/IGF -> senescence); thus high glucose will cause endothelial senescence; but not just that....intake of cholesterol rich food; they might increase HDL...but all in all, they increase LDL; it's not cholesterol; saturated fats too/Trans Fats/Hydrogenated Fats Poison; albeit PUFAs (polyunsaturated fats) can have benefitial effects; such DHA/EPA/LNA who all reduce atherosclerosis (by making better mito membrane fluidity kinetic and will reduce mitochondrial ROS- simply because more fluid; because long-chain PUFAs are highly ROS susceptible themselves (but, they are mitigated by Anti-Oxidant Systems and by 'offsetting' their presence by combining the composition with Small-Chain PUFAs/MUFAs (Monounsaturates)). Thus, atherosclerosis is also caused by macrophage ROS (macrophages produce ROS, both alive and senescent; including during phagocytosis), this will cause endothelial Lipoperoxidation, not just glucose/glycoxidation....formation of 7-ketocholesterol and other oxidized forms of LDL/HDL...the TAC/ORAC (Total Antioxidant Capacity/Oxygen (Oxide) Radical Absorbance Capacity) will be too low for HDL/LDL..thus the Lag Time of them will be reduced (lag time means how long they are protected/Anti-oxidized - Until they become 'Oxidized (when TAC/ORAC is too depleted))...people that don't have atherosclerosis have higher total antioxidant capacity in their artery/endothelium/Vasculature/blood/albumin (albumin is magnesium rich and contains high TAC/ORAC; it is a source of protectiong by its TAC/ORAC)....thus longer LagTime (longer time before nearly full TAC/ORAC consumption; once they are consumed, ROS will elevate dramatically and oxidized molecules from exosure to them, too), if there is accumulation of senescingg macrophages futilely trying to mop up LDL/they consume it/but accumulating, formaing a enlarging LDL fat pocket in atherolesion (and producing ROS during senescence and during their invasion of the artery; the immune cells (like macrophages) are capable of creating ROS - as a double-edged fighting mechanism 'fight fire with fire' and 'try not to burn yourself' (not just phaging/eating; but oxidizing using ROS; immune cells can kill cancer cells with ROS (natural killer cells/t-cells/macrophages can weaponize ROS for themselves against whatever 'intruder cell'; autoimmunity diseases are oftenly when the immune system overdoes it/hyper - and then auto-destroys the host 'attacking self by error'/and then itself...thus even immune system can destroy healthy tissues by ROS production) and then consume/phage them). The macrophages if they functioned correctly and not invasively/uncontrollably; then they would phage things correctly, such as oxidized molecules/excess cholesterol, and ROS would then reduce because function would be restored.

I noticed that it is not because I reduced sugar/carbs intake (although I did notice, that Excess carbs was Very detrimental to arterial function - causing me hypoxic events in vasculature, ischemic events...which are deadly and can cause necrosis/death of tissue of not enough O2 in that artery...endothelial cells will die; high glucose increase HIF-1a (Hypoxia Inducible Factor) to improve cell viability under Lowering O2 levels; thus it is very protective under lacking of oxygen...but...there is maximum to that; and at a certain point too Low O2 -> dropping ATP levels in mitos...and this can cause Premature/Abrupt Stress-induced senescence of cells....exiting from the cell cycle prematurely (by activation of sudden p53 oncogene)). Ischemia is lack of O2 to organs...that happens in very high blood glucose when having atherosclerosis..this can cause tissue/organ death (may become fatal). With that said, what truly was very insidious/harmful was this excess cholesterol LDL etc....that was Definitely causal to atherosclerosis. Diabetes/hyperglycemia just hastened it.

Just a 2 cents.

Posted by: CANanonymity at August 12th, 2020 9:19 PM

PPS: That's a solid take Michael...it means we may be underestimating (the LDL as contributor) in atherosclerosis and that it is -Not- always good to reduce LDL depending on the state/situation/atherosclerosis advancement of the person. But the strategy itself it still to be considered. It's really on case/per person basis; to see if LDL reduction intervention would help or be detrimental. Studies are so conflicted/contradictory (and as you said because they don't do Long Term studies..but just short term that have less meaning/impact; since atherosclerosis is a very long term disease...that need a very long term intervention/protocol/lifestyle diet change... to reverse it). This is why they may say : ''LDL reduction is futile/useless -> no reduction in mortality''....the LDL reduction strategy (while trying to boost HDL) is still very much viable strategy, same as statins; but, as you said, it may not apply to all patients... depending on their status. It means a very Personal/Custom- Long Term Intervention (personlized to/per person) to save them from the disease. Just a 2 cents.

Posted by: CANanonymity at August 12th, 2020 9:48 PM

@Michael

"See the consensus statement from the European Atherosclerosis Society Consensus Panel that low-density lipoproteins cause atherosclerotic cardiovascular disease for more evidence."

More evidence that Amgen, AstraZeneca, Eli Lilly, Merck, Novo-Nordisk, Pfizer, Unilever, Regeneron/Sanofi. E.B etc etc paid for this "consensus " Scroll down and see the Funding-
Conflict of interest.

Posted by: Wessc at August 13th, 2020 7:57 AM

Compared to what exactly

Posted by: J at August 13th, 2020 10:50 PM

"In most fields of science the existence of contradictory evidence usually leads to a paradigm shift or modification of the theory in question, but in this case the contradictory evidence has been largely ignored simply because it doesn't fit the prevailing paradigm."

Unfortunately, most physicians are not scientists, and almost always follow the prevailing paradigm, for a variety of reasons unrelated to the latest evidence.

Posted by: dtkamp at August 14th, 2020 7:54 AM

How do the Japanese deal with this condition and they are more likely to recommend eating cold water fish 3 times a week rather than reaching for the statin bottle. Glucose spikes in sensitive people is the real cause of heart disease not ldl my opinion watch medical frontiers on NHK world tv covers many topics on health in english and its always refreshing to get the best answer not the best answer money can buy

Posted by: Frederick at August 16th, 2020 11:18 AM

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