High Cholesterol

Context

Why does high cholesterol matter and what’s the connection with heart disease?

Cardiovascular (heart) disease is the leading cause of death in the world. It's a complex process, but one of the major risk factors is high cholesterol or, more specifically, elevated levels of atherogenic “lipoproteins,” cholesterol-containing molecules that contribute to atherosclerosis (the buildup of fats, cholesterol, and other substances within blood vessel walls).

What are high cholesterol symptoms?

High cholesterol has no symptoms, but a simple blood test can detect this risk factor for heart disease.

What is meant by LDL and HDL and why do they matter?

Cholesterol is not water-soluble, so it needs to be packaged with a protein transporter, a “lipoprotein,” to move through the blood. These lipoproteins are categorized by their density.

Low-density lipoprotein (LDL) particles transport cholesterol from the liver to the different tissues of the body. Unfortunately, the LDL particles can also deposit cholesterol within the vessel wall, starting the process of atherosclerosis.

High-density lipoprotein (HDL) particles, on the other hand, transport cholesterol from different tissues back to the liver for processing or excretion. This includes harvesting cholesterol deposited within the vessel wall by the LDL, decreasing its cholesterol burden.

How does cholesterol contribute to cardiovascular disease?

Cholesterol deposited within the walls of blood vessels can trigger an inflammatory cascade leading to plaque formation, an early step in cardiovascular disease. The relationship between plaque progression and symptomatic disease is multifactorial.

Studies show a more rapid progression to clinical cardiovascular disease (heart attack, angina, sudden cardiac death, stroke) in patients with a greater number of risk factors such as advanced age, smoking, diabetes, high blood pressure, and elevated cholesterol.

What other factors matter when considering whether or not a person’s cholesterol puts them at higher risk for disease?

Other factors that contribute to an increased risk of cardiovascular disease are advanced age, high blood pressure, diabetes, metabolic syndrome, family history of heart disease, other inflammatory diseases, elevated high sensitivity c-reactive protein (hs-CRP), ethnicity, and kidney disease.

Can you talk about “residual risk” and why this is such an important concept in understanding cholesterol treatment?

Imagine you’re treating someone at high risk for cardiovascular disease, and you put them on a statin (a class of medication commonly used for high cholesterol). You’ve likely decreased their risk of having a heart attack by 25-30% (compared to their elevated baseline risk), but they still have a higher risk compared to average, or what we call “residual risk.” So why doesn’t the statin decrease the risk to baseline?

First, we’re addressing the disease too late in the process, and there are vessels that are damaged beyond repair. (Cardiovascular disease can start in people’s 20s, so if we only begin to address it in people’s 50s, we may not be able to influence the disease process as much as we’d like.)

Second, we’re looking at only a small part of the big picture. We’re treating cholesterol, which may only be one part of a more complex disease process.

What about HDL, “good cholesterol”?

Previously, experts believed that elevated HDL cholesterol levels were always beneficial. Recent studies, however, showed that increasing these levels with medication did not decrease cardiovascular disease in patients, suggesting that the ability of HDL particles to transport cholesterol was more important than the number alone. Unfortunately, we don’t have a way to measure this function yet.

Testing

Are lab tests useful?

Basic lab tests can help identify those patients who are at higher risk for cardiovascular disease. However, they don’t give the whole picture. Many patients have “normal” cholesterol but, hiding under the surface, have a high risk of developing heart disease.

For example, the basic lipid panel does not measure Lp(a), a recently recognized independent risk factor for cardiovascular disease that affects one out of five people, globally.

What other factors matter?

Medical providers should realize which patients need further testing beyond the basic lipid panel. Certain patients might have a normal cholesterol, but an increased number of lipoprotein particles, for instance. The particle number does not appear on basic tests, but has been shown to be a better predictor of cardiovascular disease than LDL cholesterol.  

Since particle number and atherogenicity are so much more important, should we even order a basic lipid panel anymore?

A basic lipid panel is sufficient for most patients, but it’s important to understand exactly what it is telling us and its limitations. The key takeaway is that several factors work together to create an accurate picture of cardiovascular risk, so no one test is going to provide all the information we need.

What other data points might give us a more complete picture?

The traditional focus has been primarily on LDL cholesterol. We should be looking at ApoB (LDL and other plaque-forming particles) and expanding our view beyond cholesterol to other inflammatory markers and insulin resistance. Also, certain genotypes (such as ApoE4) may put people at higher risk because they’re more likely to form plaque, and/or plaque may be more dangerous when it’s formed.  

Medical Treatment

What medications are used for high cholesterol?

The most common medications prescribed for high cholesterol are statins. These work by reducing the body’s production of cholesterol. Other medications lower high cholesterol by decreasing intestinal absorption of cholesterol (ezetimibe/Zetia), promoting cholesterol disposal (resins such as cholestyramine), increasing cell uptake of LDL cholesterol (PCSK9 inhibitors such as Repatha), or lowering triglycerides (fibrates).

There have been a lot of changes in the recommendations for statin use in the treatment of hyperlipidemia. Who should actually be on a statin?

The previous guidelines for prescribing statins were criticized for overestimating who would benefit. The American Academy of Cardiology recently released their updated recommendations to help medical providers determine who would most benefit from cholesterol management, and identify which tools are available to reach this goal. The AAC now focuses more on creating an individualized risk profile for the patient, rather than solely relying on risk calculators.

For those already taking a statin who may not meet the updated criteria, how do you decide if it’s a medication they should stay on?

Previous guidelines may have placed less emphasis on other risk factors, such as family history and ethnicity. As mentioned before, cardiovascular disease is a complicated process that evolves over decades, and many things need to be taken into account. I recommend that patients discuss their risk for heart disease with their provider to decide whether statins is appropriate to meet their goals.

Will all people benefit to the same degree from an intervention?

No. The degree of benefit depends on multiple factors that have not only a great deal to do with genetics, but also with the stage of the disease.

For example, an 80-year-old with a 20-year history of heart issues will benefit less from an intervention than would a 40-year-old with no symptoms. By the same token, a healthy 70-year-old might benefit more than a 50-year-old diabetic who smokes.

Moreover, someone with a genetic predisposition to absorb more cholesterol will benefit more from dietary modification than the average person. Luckily, we have many tools to individualize treatment in an iterative fashion.

Lifestyle Approaches

How much do diet and exercise matter and why?

Diet and exercise form the foundation of good health, and their importance in retarding cardiovascular disease cannot be overstated. Multiple studies have investigated and proven that diet and exercise reduce the risk for cardiovascular disease by decreasing LDL cholesterol, blood pressure, waist circumference, and insulin resistance.

What are your top recommendations for diet and exercise intervention?

Diet, exercise, sleep, and emotional health are the pillars of good health and should all be optimized in order to decrease the risk of any illness, including cardiovascular disease. Here is how this translates:

First, avoid the standard American diet (high intake of red meat, processed and fried foods, refined carbohydrates, and high-sugar drinks), and look instead to the Mediterranean diet(fish, vegetables, whole grains, nuts, olive oil), as well as to increasing fiber intake. Also, smoking lowers HDL, so if you’re a smoker, get started on quitting.

Second, exercise every day, and avoid weight gain (which shifts the cholesterol balance more toward LDL). Do something you enjoy, and incorporate both aerobic and resistance exercise into that routine.

Third, try to get at least 7.5 hours of sleep, and prioritize exercise and diet over work. If your work prevents you from optimizing these things then it’s—literally—killing you.

It used to be thought that since eggs had cholesterol, those should be avoided. Is that science actually true?

The short answer is no. For most people, the amount of cholesterol in the diet does not appreciably affect the amount of cholesterol in your system. There are many feedback mechanisms that maintain cholesterol balance.

What about consuming omega-3 fatty acids to reduce cholesterol?

Several studies show that increased dietary intake of DHA and EPA omega-3 oils decreases cardiovascular mortality. However, there is great debate regarding the health benefits of taking omega-3 fatty acid supplements.

Do any supplements have an effect in lowering cholesterol?

Weight loss supplements can have varying amounts of effect on the lipid profile. However, outcomes studies have not been done.

Red yeast rice is a popular supplement used to decrease cholesterol. The active ingredient in this supplement, monacolin K, is identical to the chemical found in a statin medication called lovastatin. So, essentially, people who take red yeast rice are taking an unregulated form of a prescription drug that is of unknown quantity and quality with the same benefits and risks.

If people are on a statin and their cholesterol is low, do diet and exercise matter?

If cholesterol levels have been optimized, then diet and exercise are still important as they address other health parameters that can increase risk for cardiovascular disease. These include, insulin resistance, diabetes, obesity and high blood pressure.

What’s the new science in cholesterol? Does cholesterol alone matter as much as we used to think?

On a broad basis, we now accept that predicting who is at risk for cardiovascular disease is more complicated than plugging numbers into a calculator and basing treatment on the result. The cause of cardiovascular disease is multifactorial, and the goal is to minimize each of those factors and stack the deck in our favor.

Additionally, studies continue to support the importance of Lp(a) as an independent risk factor for heart disease. Lp(a) is an LDL particle with an added glycoprotein attached to it, rendering it more likely to cause plaque (atherogenic) and more resistant to lowering by most pharmaceuticals. The level is largely genetically determined, and there are still challenges with laboratory quantification.

What’s your personal approach to treatment?

From my point of view, everyone will suffer from cardiovascular disease at some point in their lives (whether it’s at 50, 80, or 110), so we could all benefit by minimizing risk factors. I use the 2018 ACC/AHA guidelines to help determine who is at increased risk for earlier occurrence of this disease and, thus, who needs more aggressive treatment.

I then look for other aspects of the patient’s health that may contribute to an increased risk of heart disease, such as the triglyceride and the non-HDL cholesterol level. An elevation in either of these may point to a discordance between the LDL cholesterol and the number of atherogenic particles. If I suspect this, I’ll ask for an ApoB level or a LDL particle number.

Additionally, I look at hs-CRP and lipoprotein(a) (Lp(a)), which are independent risk factors for heart disease. I may use a risk calculator, such as Framington, Pooled Cohort, or Reynolds, to further elaborate on the total picture. Finally, I present the patient with the tools available to decrease their risk, and we come up with a strategy to optimize their health.

Useful Links

Compilation of heart disease facts and statistics (CDC)

Cardiovascular disease overview (American Heart Association)

2018 guidelines for managing cholesterol  (American College of Cardiology)

Lifestyle approaches for reducing cardiovascular risk (Circulation)

A video lecture on insights (Foundation for Health Improvement and Technology)