Decreasing cholesterol: drugs and diet

There is a persistent belief that lifestyle can take care of all cholesterol problems. Lifestyle can make things worse, but once things are worse, it cannot make things better.

Once you have disease, or cholesterol is higher, you need treatment often beyond lifestyle management.

This distresses many people, who wish to have control over their fate.

High cholesterol is one of the main causes of heart attacks, strokes, and peripheral vascular disease. You can lower cholesterol through diet and exercise by as much as 15 percent. Lifestyle changes are the first choice to decrease cholesterol. Modern drugs, however, will lower cholesterol levels far more than diet or exercise.

The progressive changes of a vessel

The normal artery, as shown below, is a free-flowing blood vessel. When a person is in their late teens, there is already fatty formation on the inside of the vessel wall.

As more fat is deposited in the vessel wall, blood flow decreases, leading to ischemia in the end organ.

Angina, or heart pain, occurs when there is insufficient blood flow to the heart secondary to an artery narrowed by plaque.

Factors contributing to atherosclerotic plaque formation

Damage to the blood vessel begins the process of

• Smoking
• Hypertension
• High blood sugars
• Diets rich in saturated fats and refined grains

However, the lower the level of LDL, the less risk those factors become, as you shall see.

Anatomy of the Blood Vessel

If you examine the autopsy specimen of the coronary artery above, the blood flows through that lumen. The inner wall, the wall the blood comes into contact with, is called the endothelium. There are three layers to the wall of an artery:

1. Tunica intima
2. Tunica Media
3. Tunica Adventicia

Atherosclerosis begins when the cholesterol transport protein enters the wall of the tunica media, whose first layer is the endothelium.

Discovery of LDL

In 1954, Dr. John Gofman reported the discovery of LDL and HDL. These were the particles found when he separated plasma cholesterol-carrying lipoproteins with an ultracentrifuge. Gofman was the first to note that heart attack patients had high LDL levels. The correlation of high LDL and heart attacks has been called “one of the most profound epidemiologic correlations in all of medicine.”

High LDL levels have been shown to correlate with atherosclerosis in all species studied.

High LDL and Atherosclerosis

The higher the LDL level, the faster atherosclerosis develops. Factors that increase atherosclerosis are those which injure blood vessels: smoking, hypertension, hyperglycemia, and genetic factors that predispose endothelium to early injury.

High LDL levels can lead to heart attacks in children as young as 6 years old. This rare form of homozygous familial hypercholesterolemia inspired Brown and Goldstein to elucidate the genetic defect in the receptor for LDL.

Discovery of the LDL receptor defect

 Brown and Goldstein discovered that when LDL receptors are defective, it leads to the following:

1. LDL particles circulate for a long time
2. This leads to an increase in plasma levels of LDL
3. As a result, more deposits are made into the arteries
4. Creating atherosclerotic plaques

Lowering LDL by feedback

To keep blood LDL constant, your body uses a feedback mechanism. As your LDL levels increase, the target tissues produce more receptors to take up the LDL. If the LDL receptor is defective, the liver continues to increase production of LDL.

Brown and Goldstein speculated that an HMG CoA reductase inhibitor would deprive liver cells of endogenous synthesis as a source of cholesterol. This deprivation would relieve the feedback repression of LDL receptors, and the resultant increase in LDL receptors would lower plasma LDL.

Developing the first statins

The FDA approved the first statin 1987, Mevacor, which reduced plasma levels of LDL and was well tolerated. It was only theory that lowering LDL would reduce heart attacks.

Statins Reduce Heart Attacks and Prolong Life

Statins block cholesterol synthesis, which causes the cell to increase LDL receptors, which further decrease cholesterol in blood plasma.

The first study showing that statins not only reduce LDL, decrease heart attacks, and prolong life was reported in 1994. These studies have been repeated:

1. 1996 Sachs reported use of Pravastatin on heart attacks with normal cholesterol levels
2. 1998, LIPID showed prevention of heart attacks with a wide range of cholesterol levels
3. 2002, Heart protection by cholesterol lowering in over 20,000 high-risk people in a randomized placebo control trial

The 2002 study was large enough to show a reduction in relative risk even when subjects had risk factors such as diabetes, hypertension, and smoking.

For each reduction of LDL cholesterol by 40 mg /dl, cardiovascular events are reduced by 20%. This even applies to people considered low-risk (ref).

Better Genetics

In addition to people who have high cholesterol, there are those who have naturally low levels of cholesterol. These individuals live long lives with abnormally low levels of heart disease, even if they have other risk factors (ref). Yes, I want this mutation!

This genetic mutation led to a new class of drugs to decrease cholesterol, the PCSK9 class of drugs.

Lowering LDL over time is the key

Genetic studies, statin studies, and PCSK9 studies show that lowering LDL longer leads to lower atherosclerotic disease.

People with PCSK9 mutations may never develop atherosclerotic plaque because they have low LDL levels throughout their lives.

In many statin studies, patients were treated only when they were at high risk of coronary disease, which means they had already established atherosclerosis. Once the disease is diagnosed, patients may need a much more severe LDL reduction to prevent an event.

Bringing it back to Ancel Keys

One of the cohorts that Ancel Keys studied was in a coastal village in Japan. The men in that village had a 90% reduction in their LDL. This lifelong reduction also led to a 90% reduction in their cardiac mortality. (ref) . The PCSk9 mutations also resulted in a 90% reduction in mortality from a similar reduction in LDL.

Inflammation and cholesterol

Lowering cholesterol reduces the risk of heart disease, independent of inflammation. While some choose to blame inflammation alone as a cause of atherosclerosis, it is less a cause and more a result. Inflammation is important to repair of tissues but is not the cause of the trauma. Reducing LDL reduces the risk of heart disease.

Inflammation and oxidized cholesterol have been speculated as a cause of heart disease.

Red Meat

Red meat is nutritionally and calorie-rich. But it is also rich in saturated fat. Saturated fat leads to high blood cholesterol. And high blood cholesterol leads to plaque in the arteries. One does not need to give up meat. But, limiting red meat to four ounces a day is protective.

Vegetables and other fiber-rich foods provide an additional protective effect with the consumption of meat. It appears that the increase in soluble fibers, as well as phytoestrogens from the fiber, reduce the pathway of cholesterol absorption. In addition, they decrease the risk of colon cancer.