OVERVIEW

• A study of 400,000 middle-aged people (average age 51) shows that above-normal cholesterol levels are associated with a significant increase in the risk of cardiovascular disease in the decades that follow.
• This risk is particularly high in people who were under the age of 45 at the start of the study, suggesting that prolonged exposure to excess cholesterol plays a major role in increasing the risk of cardiovascular disease.
• Reducing cholesterol levels as early as possible, from early adulthood, through lifestyle changes (diet, exercise) can therefore limit the long-term exposure of blood vessels to atherogenic particles and thus reduce the cardiovascular events during aging.

It is now well established that high levels of cholesterol in the bloodstream promote the development of atherosclerosis and thereby increase the risk of cardiovascular events such as myocardial infarction and stroke. It is for this reason that the measurement of cholesterol has been part of the basic blood test for more than 30 years and that a deviation from normal values is generally considered a risk factor for cardiovascular disease.

Remember that cholesterol is insoluble in water and must be combined with lipoproteins to circulate in the blood. Routinely, the way to determine cholesterol levels is to measure all of these lipoproteins (what is called total cholesterol) and then distinguish two main types:

1. HDL cholesterol, colloquially known as “good cholesterol” because it is involved in the elimination of cholesterol and therefore has a positive effect on cardiovascular health;
2. LDL cholesterol, the “bad” cholesterol because of its involvement in the formation of atherosclerotic plaques that increase the risk of heart attack and stroke.

LDL cholesterol is difficult to measure directly and its concentration is rather calculated from the values determined for total cholesterol, HDL cholesterol and triglycerides using a mathematical formula:

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However, this method has its limits, among other things because a large proportion of cholesterol can be transported by other types of lipoproteins and therefore does not appear in the calculation. However, it is very easy to measure all of these lipoproteins by simply subtracting HDL cholesterol from total cholesterol:

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This calculation makes it possible to obtain the concentration of what is called “non-HDL” cholesterol, i.e. all of the atherogenic lipoproteins that are deposited at the level of the wall of the arteries and form atheromatous plaques that significantly increase the risk of cardiovascular problems. Although clinicians are more familiar with LDL cholesterol measurement, cardiology associations, including the Canadian Cardiovascular Society, now recommend that non-HDL cholesterol also be used as an alternative marker for risk assessment in adults.

Short-term risks
The decision to initiate cholesterol-lowering therapy depends on the patient’s risk of experiencing a cardiovascular event in the next 10 years. To estimate this risk, clinicians use what is called a “risk score” (the Framingham risk score, for example), a calculation based primarily on the patient’s age, history of cardiovascular disease, family history and certain clinical values ​​(blood pressure, blood sugar, cholesterol). For people who are at high risk of cardiovascular disease, especially those who have suffered a coronary event, there is no hesitation: all patients must be taken care of quickly, regardless of LDL or non-HDL cholesterol levels. Several clinical studies have shown that in this population, the main class of cholesterol-lowering drugs (statins) helps prevent recurrences and mortality, with an absolute risk reduction of around 4%. As a result, these drugs are now part of the standard therapeutic arsenal to treat anyone who has survived a coronary event or who has stable coronary heart disease.

The same goes for people with familial hypercholesterolemia (HF), a genetic disorder that exposes individuals to high levels of LDL cholesterol from birth and to a high risk for cardiovascular events before they even turn 40. A study has just recently shown that HF children who were treated with statins at an early age had a much lower incidence of cardiovascular events in adulthood (1% vs. 26%) than their parents who had not been treated early with statins.

Long-term risks
However, the decision to treat high cholesterol is much more difficult for people who do not have these risk factors. Indeed, when the risk of cardiovascular events over the next 10 years is low or moderate, the guidelines tolerate much higher LDL and non-HDL cholesterol levels than in people at risk: for example, when we usually try to keep LDL cholesterol below 2 mmol/L for people at high risk, a threshold twice as high (5 mmol/L) is proposed before treating people at low risk (Table 1). In this population, there is therefore a great deal of room for maneuver in deciding whether or not to start pharmacological treatment or to fundamentally change lifestyle habits (diet, exercise) to normalize these cholesterol levels.

Table 1. Canadian Cardiovascular Society guidelines for dyslipidemia treatment thresholds. *FRS = Framingham Risk Score. Adapted from Anderson et al. (2016).

This decision is particularly difficult for young adults, who are generally considered to be at low risk of cardiovascular events over the next 10 years (age is one of the main factors used for risk assessment and therefore the younger you are, the lower the risk). On the one hand, a young person, say in their early forties, who has above-normal LDL or non-HDL cholesterol, but without exceeding the recommended thresholds and without presenting other risk factors, probably does not have a major risk of being affected by a short-term cardiovascular event. But given their young age, they may be exposed to this excess cholesterol for many years and their risk of cardiovascular disease may become higher than average once they turn 70 or 80.

Recent studies indicate that it would be wrong to overlook this long-term negative impact of higher-than-normal non-HDL cholesterol. For example, it has been shown that an increase in non-HDL cholesterol at a young age (before age 40) remains above normal for the following decades and increases the risk of cardiovascular disease by almost 4 times. Another study that followed for 25 years a young population (average age of 42 years) who presented a low risk of cardiovascular disease at 10 years (1.3%) obtained similar results: compared to people with normal non-HDL cholesterol (3.3 mmol/L), those with non-HDL cholesterol above 4 mmol/L had an 80% increased risk of cardiovascular mortality.   As shown in Table 1, these non-HDL cholesterol values are below the thresholds considered to initiate treatment in people at low risk, suggesting that hypercholesterolemia that develops at a young age, even if it is mild and not threatening in the short term, may nevertheless have longer-term adverse effects.

This concept has just been confirmed by a very large study involving nearly 400,000 middle-aged people (average age 51) who were followed for a median period of 14 years (maximum 43 years). The results show a significant increase as a function of time in the risk of cardiovascular disease based on non-HDL cholesterol levels: compared to the low category (<2.6 mmol/L), the risk increases by almost 4 times for non-HDL cholesterol ≥ 5.7 mmol/L, as much in women (increase from 8% to 34%) as in men (increase from 13% to 44%) (Figure 1).

Figure 1. Increased incidence of cardiovascular disease based on non-HDL cholesterol levels. From Brunner et al. (2019).

The largest increase in risk associated with higher non-HDL cholesterol levels was observed in people who were under 45 years of age at the beginning of the study (risk ratio of 4.3 in women and 4.6 in men for non-HDL cholesterol ≥5.7 mmol/L vs. the reference value of 2.6 mmol/L) (Figure 2). In older people (60 years or more), these risk ratios are much lower (1.4 in women and 1.8 in men), confirming that it is prolonged exposure (for several decades) to high levels of non-HDL cholesterol that plays a major role in increasing the risk of cardiovascular disease.

Figure 2. Age-specific and sex-specific association of non-HDL cholesterol and cardiovascular disease. From Brunner et al. (2019).

According to the authors, there would therefore be great benefits in reducing non-HDL cholesterol levels as soon as possible to limit the long-term exposure of blood vessels to atherogenic particles and thus reduce the risk of cardiovascular events. An estimate based on the results obtained indicates that in people 45 years of age and under who have above-normal non-HDL cholesterol levels (3.7–4.8 mmol/L) and other risk factors (e.g. hypertension), a 50% reduction in this type of cholesterol would reduce the risk of cardiovascular disease at age 75 from 16% to 4% in women and from 29% to 6% in men. These significant reductions in long-term risk therefore add a new dimension to the prevention of cardiovascular disease: it is no longer only the presence of high cholesterol levels which must be considered, but also the duration of exposure to excess cholesterol.

What to do if your cholesterol is high
If your short-term risk of cardiovascular accident is high, for example, because you suffer from familial hypercholesterolemia or you combine several risk factors (heredity of early coronary artery disease, hypertension, diabetes, abdominal obesity), it is certain that your doctor will insist on prescribing a statin if your cholesterol is above normal.

For people who do not have these risk factors, the approach that is generally recommended is to modify lifestyle habits, particularly in terms of diet and physical activity. Several of these modifications have rapidly measurable impacts on non-HDL cholesterol levels: weight loss for obese or overweight people, replacing saturated fat with sources of monounsaturated fat (olive oil, for example) and omega-3 polyunsaturated fats (fatty fish, nuts and seeds), an increase in the consumption of soluble fibres, and the adoption of a regular physical activity program. This roughly corresponds to the Mediterranean diet, a diet that has repeatedly been associated with a decreased risk of several chronic diseases, particularly cardiovascular disease.

The advantage of adopting these lifestyle habits is that not only do they help normalize cholesterol levels, but they also have several other beneficial effects on cardiovascular health and health in general. Despite their well-documented clinical utility, randomized clinical studies indicate that statins fail to completely reduce the risk of cardiovascular events, both in primary and secondary prevention. This is not surprising, since atherosclerosis is a multifactorial disease, which involves several phenomena other than cholesterol (chronic inflammation in particular). This complexity means that no single drug can prevent cardiovascular disease alone. And it is only by adopting a comprehensive approach based on a healthy lifestyle that we can make significant progress in preventing these diseases.