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.

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