Friend or foe: cholesterol’s contested role

In the body’s grand theatre of life, the heart plays a leading role. Among the cast of characters supporting its role are those that doctors have traditionally seen as “villains of the piece”. Science is dramatically changing that perception.

Low-density lipoprotein (LDL) cholesterol has long been considered a villain. Doctors called it “bad cholesterol” after research linking it as a cause of cardiovascular disease (CVD, an umbrella term for conditions that include heart attack and stroke). When LDL levels rise, many doctors still reach for the prescription pad to put patients on cholesterol-lowering drugs. The most well known and controversial are statins.

Many doctors still give high-density lipoprotein (HDL) cholesterol a free pass as “good cholesterol”, thanks to research suggesting benefit in keeping CVD risk low.

Yet it’s unscientific to talk of “good” and “bad” cholesterol as it is misleading. It ignores the complexity and nuance of cholesterol’s role in the body.

You have to have both LDL and HDL cholesterol in your body because without both, you’d be dead. Research shows that high LDL levels are not all “bad” for you as only 50% of people with high LDL end up having a heart attack. And like all good things in life, even too much “good” HDL can be bad.

A balance of LDL and HDL is proving key to optimal health in body and mind. Getting that balance right is not always a breeze. Compounding that is research showing that nitric oxide (a molecule produced by the endothelium, the inner lining of blood vessels) plays a crucial role in cardiovascular health. Nitric oxide is a powerful vasodilator, meaning it helps relax and widen blood vessels. 

Some basic biochemistry is important. Cholesterol is a waxy, fat-like substance found in every cell of your body, along with other blood fats such as triglycerides. Cholesterol is essential for numerous bodily functions, including formation of cell membranes, production of hormones (such as oestrogen and testosterone) and vitamin D synthesis. It is essential for brain health, to support the ability to think, remember and learn.

The brain is the body’s most cholesterol-rich organ. It contains about 23% of the body’s total cholesterol. Emerging research suggests that imbalance in cholesterol levels, particularly in ageing populations, may affect cognitive function and increase the risk of neurodegenerative diseases, such as Alzheimer’s and Parkinson’s.

Lipoproteins are biochemical structures consisting of lipids (fats) and proteins. Their primary function is to transport “hydrophobic” lipid (fat won’t mix with water) molecules through the bloodstream’s aqueous environment.

LDL’s main function is to transport cholesterol from the liver to cells and tissues throughout the body. Depending on particle size, small, dense LDL elevates the risk for the formation of plaque that can clog arteries and contribute to causing heart attack or stroke. It is also possible to have elevated LDL levels without immediate risk of heart disease or stroke due to other protective factors.

HDL’s primary function is to transport excess cholesterol from peripheral tissues back to the liver. This process helps remove cholesterol from the bloodstream and prevents accumulation in arteries that can lead to atherosclerosis (plaque build-up) and cardiovascular disease

But just how high must LDL levels and HDL cholesterol levels be before doctors want you to take drugs? Medical advice may differ significantly depending on where you live and your risk profile.

In the US, for example, cholesterol levels are measured in milligrams per decilitre (mg/dl). Official guidelines recommend statins for individuals with LDL levels of 190mg/dl or higher. In Europe, cholesterol levels are more stringent and are measured in millimoles per litre (mmol/l). Official guidelines recommend statins for those with LDL levels above 1.8 mmol/l (about 70 mg/dl) for secondary prevention (to prevent a second heart attack or stroke). Additional factors, such as chronic kidney disease and severe hypertension, may prompt statin therapy at even lower LDL levels. SA guidelines align with European standards for cholesterol management.

At the heart of all these guidelines is the “lipid or cholesterol hypothesis”: that a “raised cholesterol level causes heart disease”. It is not an overnight sensation. It first emerged in the early 20th century in the foundational work of Russian pathologist Nikolai Anichkov in 1913. It gained further traction through the work of US physiologist Ancel Keys in the 1940s and 1950s, culminating in his influential (and largely discredited) Seven Countries Study.

For evidence of where Keys went wrong, read the Big Fat Surprise, Why Butter, Meat and Cheese Belong in a Healthy Diet by US nutrition scientist Nina Teicholz.

By the end of the 1980s, doctors widely recognised and accepted the lipid hypothesis as a central tenet in cardiovascular health. The lipid hypothesis is “possibly the single most powerful idea in medicine” that has long since reached the hallowed status of “fact”, writes Scottish GP Dr Malcolm Kendrick on his eponymous blog (drmalcolmkendrick.org). Kendrick is the author of The Great Cholesterol Con — The Truth About What Really Causes Heart Disease.

The lipid hypothesis is also “entirely resistant to all contradictory evidence”, he says.

That evidence includes a 2022 study by US researchers in Current Opinion in Endocrinology & Diabetes and Obesity. The study finds that statin therapy for primary and secondary prevention of CVD is “not warranted for individuals on a [low-carbohydrate diet] with elevated LDL cholesterol who have achieved a low triglyceride-HDL ratio”.

Lead study author Dr David Diamond, a neuroscientist at the University of Florida, has a special interest in cardiovascular research. He is unequivocal about LDL and HDL for optimum health.

There is simply “no scientific basis for fearing high LDL”, Diamond says. The literature on the value of high LDL needs to be appreciated to promote good health, he says. It is associated with “great longevity and the reduced incidence of death from cancer and infectious disease”.

“And yes, nitric oxide is important for optimal health,” says Diamond.

What we should all fear, he says, is “metabolic dysfunction, produced by smoking, obesity, hyperglycaemia and diabetes”.

The treatment landscape for high LDL cholesterol is still evolving. Statins remain first-line therapy for lowering LDL levels due to what some doctors see as “proven efficacy and safety profile”. Others quibble with that profile because not all patients tolerate statins well or achieve the desired results on them alone.

Newer classes of medications have emerged, including PCSK9 inhibitors. Drug companies claim that these drugs can lower LDL levels by up to 60% beyond what statins can achieve alone.

Diamond and others promote diet as crucial role in managing LDL. And while saturated fats have long been associated with increased LDL levels, research shows that dietary cholesterol is not as harmful as once thought for most people.

Johannesburg cardiologist physician Dr Riaz Motara has some hearty last words: “HDL and LDL cholesterol are not ‘bad’. They are just performing functions they were intended to perform.”

The major problem is chronic, low-grade inflammation caused by “an unhealthy gut microbiome, too much refined sugar and processed foods in our diet, high omega 6-rich diets and chronic stress”, he says 

This causes oxidation or “inflammation” of LDL cholesterol into oxidised or small, dense LDL. The same inflammation “inflames” the inner lining of arteries, which the body attempts to heal by depositing this “sticky” form of cholesterol as a healing response, Motara says. “This attempt at healing over a long period is the real cause of the problem. Simply reducing total cholesterol won’t have an impact without managing inflammation levels.  A dual approach is needed.”

Motara sees a role for statin therapy but only as part of a comprehensive approach to reduce heart risk.  Newer drugs can manage very high-risk patients but are still “extremely expensive” to form part of a general strategy to reduce risk. Motara’s general advice is: