by Isabella Del Priore
figures by Carlos Morales

We’ve all heard it before: high cholesterol is bad and can increase your risk for heart disease. Though there is a direct association between cardiovascular disease and high cholesterol, there exists controversy and confusion over treatment options. What counts as “high” cholesterol, do I really need to cut out eggs, and which one is the “bad” one again? 

What is cholesterol and where does it come from?

Cholesterol is a waxy, fat-like substance called a sterol. Though it has a bad reputation, cholesterol is required for our bodies to function normally. It plays an essential role in maintaining proper cell membrane structure; without cholesterol, cells would lose their shape and ability to regulate what enters and exits the cell. Cholesterol also serves as a building block for important substances like hormones, vitamin D, and bile acids (which facilitate fat breakdown during digestion). (Figure 1)

The body makes all the cholesterol it requires in the liver through a tightly regulated process called the mevalonate pathway. This process takes a molecule, called acetyl CoA, and turns it into cholesterol via several steps. These steps, or reactions, are made possible by a series of proteins, called enzymes, which serve as the gatekeepers of each reaction. The reaction can only occur if the enzyme is present and in the right form. One particular enzyme, called HMG-CoA reductase, is a key component of cholesterol synthesis. Therefore, it is a drug target to moderate cholesterol levels (which will be referenced later). The other source of cholesterol is from animal products in the diet, such as meat, fish, eggs, and dairy. 

Types of cholesterol—the difference between HDL (the “good!”) and LDL (the “bad”)

The two main types of cholesterol are high-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol (LDL-C). What is a lipoprotein? Lipoproteins are spheres made up of fats (lipo-) and proteins. They serve as the vehicles that carry cholesterol through the blood. HDL-C is considered “good” because it carries excess cholesterol from the blood back to the liver where it gets broken down and taken out of the body. Conversely, harmful LDL-C moves cholesterol through the bloodstream and can build up in the arteries, leading to the formation of plaques. Plaques can narrow and block arteries, cutting off blood flow to essential organs, like the heart or brain, increasing risk of cardiovascular disease. (Figure 2)

The link between cholesterol and cardiovascular disease

Cardiovascular disease (CVD) remains the number one cause of death worldwide. CVD encompasses multiple conditions affecting the vascular system, specifically decreasing blood flow to the heart (heart disease and heart attack) or the brain (stroke). To better understand CVD risk factors, the National Institutes of Health (NIH) embarked on what became a multi-generational, ongoing study called the Framingham Heart Study. Started in 1948, the study has amassed data from over 14,000 individuals and demonstrated that high cholesterol is a risk factor for CVD. 

The Framingham Heart Study helped establish monitoring of cholesterol levels as a routine blood test. Currently, it is advised that total cholesterol, which includes LDL, HDL, and other forms of cholesterol, be at or below 200 milligrams per deciliter (mg/dl), with LDL-C levels under 100 mg/dl. In the absence of other risk factors (such as diabetes, history of heart attack, high blood pressure, or being a smoker), doctors likely won’t consider treatment unless LDL-C levels are above 190 mg/dl.

It has been shown that lowering LDL-C reduces risk for CVD. In the groundbreaking 4S clinical trial, patients with high LDL-C received statins, a class of cholesterol lowering drugs, which decreased LDL-C levels by 35% and cardiovascular events by 34%, a dramatic reduction not seen previously. This trial was the starting point for a series of studies that similarly showed positive results for patients on statins.  

But isn’t cholesterol important for normal cellular function? Wouldn’t lowering LDL-C too much be an issue? Clinical trials have shown that continuing to lower LDL-C is safe, and significant negative effects were not observed in patients. There was even a trial with LDL-C levels lower than 30 mg/dl; the safety profile remained favorable after 6 years of follow-up. 

What do statins do and are there side effects?

You may have heard of statins, as they are the most widely prescribed LDL-C lowering medication. As alluded to previously, inhibiting the enzyme HMG-CoA reductase is a way to target cholesterol synthesis, which is how statins work. Preventing the function of this enzyme blocks the pathway that makes cholesterol, resulting in a reduction of cholesterol levels within cells. When there is less cholesterol in cells, cells are triggered to increase a surface protein called an LDL receptor. This protein then takes LDL-C out of the blood and into cells, lowering blood LDL-C levels. Additionally, statins can increase the amount of HDL-C.  

Despite their positive effects, statins frequently receive bad press regarding side effects, such as muscle aches, diabetes, and brain fog. Though side effects have been observed in some patients, they are rare, and the exact causal link has not been established. Most muscle symptoms and cognitive effects are resolved by adjusting the statin dose or type, or by stopping medication. The development of diabetes generally occurs in patients who already have additional risk factors. Overall, the benefits of reducing LDL-C and CVD risk via statins seem to outweigh potential negative side effects.

Can lifestyle changes really make a difference?

Before suggesting a patient make the long-term commitment to take medication, doctors often recommend lifestyle changes to improve cholesterol levels. But, do changes in diet and exercise truly make an impact? The answer is not so straightforward. It is agreed upon that a healthy diet is beneficial for overall health, including cardiovascular health. The controversy lies in whether consuming dietary cholesterol is directly linked to CVD risk. Different studies have both supported and refuted the common myth that eating too many eggs raises blood cholesterol levels. Despite lack of concrete evidence of the effects of dietary cholesterol, it is known that reducing saturated fats (often present in foods high in cholesterol) is beneficial for cardiovascular health. Dietary recommendations include eating less red meat and full-fat dairy products and following a Mediterranean diet. 

Beyond diet, exercise is an essential part of maintaining good health. There is a correlation between exercising more and increasing HDL-C while maintaining or lowering LDL-C. The reason why, however, is still not fully understood. (Figure 3)

Now what?

What is known about cholesterol and its link to cardiovascular health has demonstrated that high LDL-C necessitates attention. Treatment may look different for each patient, but maintaining a healthy lifestyle and the subsequent addition of statins, if necessary, shows safety and efficacy. 

If statins and lifestyle changes don’t work for a patient, a newer class of drugs, PCSK9 inhibitors, offers a promising alternative. Instead of blocking the synthesis of cholesterol like statins, PCSK9 inhibitors increase the amount of LDL-C receptors on the surface of cells. This results in more LDL-C being taken out of the blood.

Overall, the “right” treatment to pursue when diagnosed with high cholesterol depends on more than a series of numbers from a blood test. It is important to take into consideration the whole person, including cardiovascular disease risk factors and lifestyle choices, to come to a decision that both the patient and doctor feel comfortable with. But for now, the evidence seems to suggest that you can probably continue to have your eggs at brunch (in moderation, of course). 

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Isabella Del Priore is a first-year PhD student in the Biological and Biomedical Sciences program at Harvard Medical School. You can find her on Twitter @i_delpriore. 

Carlos Morales is a first year PhD student at the Systems, Synthetic and Quantitative Biology program at Harvard Medical School. You can find him on Twitter @solracTV and on LinkedIn.

Cover image by FotoshopTofs on pixabay.

For More Information:

• To read a summary of statins clinical trials over the years, click here.
• Check out this review for more details on the side effects of statins. 
• Visit the Framingham Heart Study website here.
• To learn more about the impact of diet on cholesterol levels from the American Heart Association, click here.