Why Lower LDL-Cholesterol?8 minute read

Steven Kornweiss, MD cardiovascular, lipidology, preventive medicine Leave a Comment

A Remarkable Discovery

In 1978, a pathologist performing a routine autopsy made a remarkable discovery — A 76 year old woman without any sign of atherosclerosis.

What’s so remarkable about this?

Autopsy studies have revealed that by age 70, most people have raised atherosclerotic lesions covering 20-60% of the intimal surface of the coronary arteries and aorta (source).

The authors of this study hypothesized that this woman had a rare condition that made her resistant to atherosclerosis.

Atherosclerosis is a gradual degenerative process whereby lipoproteins (and their cholesterol) deposit within the arterial wall and an inflammatory response ensues. The wall of the artery thickens over time and plaques form. These plaques can enlarge and encroach upon the vessel lumen, limiting blood flow to vital organs like the heart muscle itself. Eventually, plaques can rupture and cause thrombosis and occlusion of an artery, which results in total lack of blood flow and oxygen to whatever it supplies. If this happens in a sufficiently large coronary artery, a deadly heart attack can result.

Atherosclerotic heart disease kills one in eight Americans each year. Contrary to the current medical paradigm, this is not a disease of the elderly. Even though most heart attacks occur in people who are past their fifth decade of life, the disease process starts in the second or third decade of life.

How do we know that atherosclerosis starts in the second and third decades of life?

In the 60s, Strong and McGill, pathologists working at the Louisiana State University School of Medicine set out to define the prevalence of coronary atherosclerosis in the general population, and to discover if atherosclerosis was in fact responsible for deadly heart attacks.

They performed 548 autopsies on patients from age 1 to 69 who died from various causes both related and unrelated to heart disease.

What they found was striking:

In the second decade of life, depending on race and gender, 30-60% of the autopsies demonstrated coronary artery atherosclerosis. By the fourth decade of life, 96% of white men, 89% of black men, 57% of white women, and 97% of black women in the study had coronary atherosclerosis. By the fifth decade of life, all but one (88 out of 89) autopsies demonstrated atherosclerosis. Of the autopsies conducted on those who died in their 50s and 60s, 100% of them demonstrated atherosclerosis.

These findings led the authors to conclude the following:

The present investigation and other studies of the coronary arteries in North Americans leave little doubt that coronary atherosclerotic lesions as well as aortic lesions are present in almost all of the adult United States population. We cannot divide our population into individuals having and those not having atherosclerosis; it can only be classified according to the degree of each type of lesion in each artery.

It is possible that the findings of this report suffer from selection bias. It’s an autopsy study, so it’s likely that those not included in the study (the living) may have less coronary disease, or none at all. The woman mentioned at the beginning of this article, for instance, lived to 76 and had no atherosclerosis. She had no chance of being included in this study by the fact that she lived to age 76. So it’s almost certain that there are others like her who are not in the study, but it is clear that they are precious few.

The study also included many people who died from accidental causes. Even in this group, atherosclerosis is ubiquitous.

How can we leverage the knowledge that atherosclerosis starts early in life?

I’d like to refer back to Strong and McGill to answer that question:

Not only do these observations support the hypothesis that ischemic heart disease is correlated with coronary artery lesions, but they also show that the stage for the epidemic of morbidity and mortality in the 40’s and 50’s is set at least 20 years earlier, long before occurrence of the terminal occlusive episode. The search for etiologic factors responsible for the basic arterial lesions, therefore, should be concentrated on this earlier age period.

In the 60s, these guys realized by looking at the arteries of people in their teens and twenties, that mitigating this deadly process needs to happen 20 years before a heart attack happens.

Prevention of a first heart attack is called “primary prevention.” Prevention of a second heart attack after a first has occurred is called “secondary prevention.”

It’s known by many doctors that atherosclerosis is a chronic disease process that starts early in life. However, primary prevention is often not taken seriously. Patients and doctors don’t feel urgency until a heart attack happens. Only then do we pay special attention to this problem.

The issue with this approach is that many first heart attacks are fatal.

Why wait for atherosclerosis to develop or to have a heart attack before trying to treat or mitigate this problem that starts decades before its final consequence?

Let’s go back to the woman who lived to age 76 with no atherosclerosis. What made her different?

In 1978 when she died, molecular diagnostics weren’t available to the doctors who studied her case, but based on her lipid panel and family history, doctors diagnosed her with hypobetalipoproteinemia (HBL).

In this condition, patients have total and LDL-cholesterol levels that are roughly 25-50% that of the average person. These patients often have genetic variations of their lipid trafficking system that result in either decreased production of ApoB particles (VLDL, IDL, LDL, Lp(a), and remnants) in the liver, or increased clearance of these particles from circulation.

Recall from prior discussions that ApoB is an apolipoprotein that sits on the surface of the LDL particle (and some other lesser known particles that I’ve listed above). Some HBL patients have a genetic variant of the ApoB protein that is truncated — it’s smaller than a normal ApoB protein. Some of these truncated variants result in fewer ApoB lipoproteins being secreted from the liver, some are cleared from the blood stream faster, and some do both. If ApoB lipoprotein secretion is lower and/or clearance is higher, serum levels of LDL will go down. If you have increased clearance of LDL particles, serum residence time (the time the LDL particle spends in circulation) will also go down.

Lower serum LDL levels and plasma residence time means there is less chance for a particle to end up in an artery wall.

Another mutation that can cause the HBL phenotype is a PCSK9 loss of function mutation.

PCSK9 is a protein with an interesting job. Its job is to bind to LDL-receptors and earmark them for degradation.

If PCSK9 is absent, deficient, or does not function properly, the liver will have more LDL-receptors on the surface of its cells. More receptors means the liver can clear ApoB lipoproteins more rapidly from the blood stream.

Patients with PCSK9 loss of function have lower serum LDL levels and their LDL particles spend less time in circulation.

PCSK9 Inhibitors

Amazingly, scientists and pharmaceutical companies have been able to mimic PCSK9 loss of function using a monoclonal antibody.

Evolocumab (Repatha) is a monoclonal antibody developed by Amgen and FDA approved in 2015 to treat patients with known cardiovascular disease or Familial Hypercholesterolemia. The drug works by binding to PCSK9 which prevents it from marking the LDL-receptor for degradation. Just like in patients with PCSK9 loss of function, patients treated with this drug have more LDL-receptors with which to remove circulating ApoB lipoproteins.

The FOURIER Trial

In the FOURIER trial, a double-blind placebo-controlled randomized clinical trial that enrolled 27,564 patients with atherosclerotic cardiovascular disease and LDL cholesterol levels of at least 70 mg/dl who were on statin therapy already.

Average LDL cholesterol for the enrollees was 92 mg/dl. Patients randomized to the PCSK9 inhibitor group ended with a median LDL cholesterol of 30 mg/dl, a 65% reduction in LDL cholesterol.

The primary end point was a composite end point of cardiovascular death, MI, stroke, hospitalization for unstable angina, or coronary revascularization. Over a 2.2 year period, the PCSK9 inhibitor group was 15% less likely to suffer the primary outcome. That is, out of 13,784 patients in the PCSK9 inhibitor group, only 1344 (9.8%) suffered the primary outcome whereas 1563 patients from the 13,780 placebo group (11.3%) suffered the primary outcome.

To have this much of a difference over just a 2 year time period is staggering.

The adverse events between groups were no different other than a small percentage of patients with injection site reactions in the PCSK9 group. These were minor and quickly resolving in nearly all cases.

Questions about PCSK9 inhibition — where does the cholesterol go?

I’ve been thinking about this drug for some time now, as well as studying the literature on patients with HBL. A few worrisome questions have arisen in my mind.

If PCSK9 inhibitors allow liver cells to express increased levels of LDL receptors, and thus take in more LDL particles, where does the cholesterol go?

Well, there are only a few places it can go.

Cholesterol can go into cell membranes, into the cytoplasm of a cell, it can go into liver cells and be converted into bile acids and then secreted into the GI system and out of the body, it can go into serum lipoproteins, or it can deposit into tissues where it doesn’t belong — like in the wall of an artery, or into the skin or tendons as seen in patients with familial hypercholesterolemia.

In some patients with HBL who have defective ApoB proteins, the liver cell cannot assemble LDL particles. So, phospholipids and cholesterol get stuck in the liver cells and accumulate, which causes hepatic steatosis (fatty liver). This can be harmful in a small percentage of cases.

There is at least one documented case in the literature of familial hypobetalipoproteinemia linked to gallstone formation in a 10 year old girl.

In extreme cases of familial hypobetalipoproteinemia, or abetalipoproteinemia, there is such a marked deficiency of ApoB lipoproteins that fat soluble vitamins cannot be delivered to the central nervous system and various neurologic and retinal deficiencies can be seen.

Amazingly, in patients with PCSK9 loss of function, and in patients taking PCSK9 inhibitors, none of these problems appear to arise.

With regard to the fate of excess total body cholesterol that must be disposed of when serum LDL-cholesterol is lowered from 90 mg/dl to 30 mg/dl on initiation of treatment with PCSK9 inhibitors, Reyes-Soffer et al. theorize that there is an initial hepatocellular uptake of this cholesterol and thereafter a new steady state is established.

That is, some excess cholesterol is taken up by the cells which are able to safely absorb this additional cholesterol, or excrete it in the form of bile salts, and the remaining cholesterol now circulates to and from the liver at a faster rate. LDL and other lipoproteins are secreted by the liver and taken back up in half or a quarter of the time prior to treatment (source.

Is it dangerous to lower LDL-cholesterol to 20-40 mg/dl?

Another concern people have about PCSK9 inhibitors is that they’re able to achieve very low levels of LDL cholesterol. Is it dangerous to have an LDL-cholesterol of 20-40 mg/dl?

No, it appears to be safe.

Most heterozygous HBL patients with LDL-cholesterol in that range have no sign of neurodegenerative disease, neurocognitive disability, or fat soluble vitamin deficiency. And, thus far, clinical trials of PCSK9 inhibitors do not show any increase in adverse events in patients achieving these low levels.

Lowering serum ApoB lipoproteins early in life should drastically reduce the chances of developing atherosclerotic cardiovascular disease.

Lowering the level of serum ApoB lipoproteins (IDL, LDL, and remnants) and speeding their removal from circulation by the liver is a very safe and effective method of slowing the development of atherosclerosis.

A few lucky people have genetic mutations that cause naturally low LDL cholesterol levels and decreased plasma residence time. Now other people can achieve the same result by taking PCSK9 inhibitors.

Not all people can, or should take PCSK9 inhibitors. Cost can be prohibitive if it’s not covered by insurance. The medication is taken by injection. Some people will have localized reactions or developed antibodies that bind to the drug. So, like any treatment, it’s not a 100% perfect cure-all. However, there are other strategies to lower ApoB lipoproteins including nutritional tactics and other pharmacologic interventions.

To minimize the life-long chance of heart attack, stroke, and other vascular diseases, I believe one (not the only) important strategy is to:

  1. Detect dyslipidemia and elevated ApoB lipoproteins as early in life as possible.
  2. Achieve low serum levels of ApoB lipoproteins in the second and third decades of life.
  3. Maintain low serum ApoB for the duration of one’s life.

-Steve

Feature Photo Credit: Cameron Venti

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