Can Further Lowering of Blood Cholesterol Save Lives?

Alcohol and Heart DiseaseFor 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.

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.