The importance of maintaining normal cholesterol levels, even at a young age

The importance of maintaining normal cholesterol levels, even at a young age

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:

[LDL cholesterol] = [Total cholesterol] – [HDL cholesterol] – [Triglycerides] / 2.2

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:

[Total cholesterol] – [HDL cholesterol] = [Non-HDL cholesterol]

This calculation makes it possible to obtain the concentration of what is called “non-HDL” cholesterol, i.e. all of the atherogenic lipoproteins [VLDL, IDL, LDL and Lp(a)] 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.

Exercise on an empty stomach to burn more fat

Exercise on an empty stomach to burn more fat

OVERVIEW

  • Sedentary men did supervised exercise 3 times a week for 6 weeks after ingesting either a sugary drink or a sugar-free placebo drink.
  • Participants who exercised on an empty stomach “burned” twice as much fat as those who consumed a sugary drink before exercise sessions.
  • Participants who exercised on an empty stomach also saw their insulin sensitivity improve more than those who ingested calories before the exercise sessions.

It is now well established that exercise in all its forms improves overall health. In addition to increasing cardiorespiratory capacity, regular exercise improves insulin sensitivity and reduces insulin secretion after meals. However, each individual’s response to similar exercises is very variable: some people become fitter or lose more weight or stabilize their blood sugar more than others. One of the factors that could be important is the timing of meals and exercise sessions. Muscles use energy in the form of sugars and fats, which can come from the last meal or from reserves in the body when fasting. The accumulation of too much fat in the muscles is problematic for health, because the fat-engorged muscles do not respond well to insulin, a hormone that stimulates the absorption of glucose by muscle, adipose and liver cells. Therefore, excess fat in the muscles can contribute to insulin resistance, hyperglycemia and increased risks of type 2 diabetes and other metabolic imbalances.

In a randomized controlled study, an international team tested the effect of the timing of meals on the metabolic benefits associated with exercise. Thirty sedentary and overweight or obese men were divided into three groups (see figure below): a control group that continued to live normally and two other groups that did supervised exercise in the morning (treadmill running), three times a week for six weeks, without breakfast; the second group ingested a vanilla-flavoured drink containing 20% sugar two hours before each exercise session, whereas the third group ingested a vanilla-flavoured placebo beverage containing water and no calories. After each morning exercise session, participants in both groups drank the beverage they had not received prior to the session. This means that all the runners ingested the same number of calories and did the same amount of exercise, only the timing of calorie consumption differed, i.e. before or after the exercise session.

Figure. Protocol schematic for the training study.  Adapted from Edinburgh et al., 2019.

The study was randomized and controlled, so participants did not know what type of drink they ingested before and after exercising. 83% of participants reported that they could not detect differences between the sugary and placebo drinks or were unable to identify which beverage contained sugar. It should be noted that the sugar used here, maltodextrin (partially hydrolyzed starch), has a very low sweetening power and is therefore difficult to detect.

Blood samples and biopsies of a muscle located in the thigh (vastus lateralis) were taken before and after the intervention in order to measure different metabolites and proteins of interest. Glucose, glycerol, triglycerides, HDL and LDL cholesterol, insulin, C-peptide, and fatty acids were measured in the blood, and phospholipid composition, protein content involved in glucose transport, insulin signalling and lipid metabolism were measured in the vastus lateralis muscle samples.

Not surprisingly, the control group did not improve their physical fitness or insulin sensitivity during these six weeks. On the contrary, the other two groups who exercised saw their fitness improved and their waistline decreased, although only a few of the participants lost weight.

The most striking finding of the study was that participants who exercised on an empty stomach “burned” twice as much fat as those who consumed a sugary drink before the exercise session. Yet participants in both groups who exercised expended the same number of calories.

Participants who ran on an empty stomach also saw their insulin sensitivity improve further and their muscles synthesized greater amounts of certain proteins (AMP-activated protein kinase, an energy sensor, and the glucose transporter GLUT4) involved in the response of muscle cells to insulin and the use of sugars.

Studies on exercise and metabolic health will need to consider the timing of meals in the future. Since it is not possible for everyone to exercise in the morning after the night fasting period, it will be interesting to check if it is possible to obtain the same metabolic benefits after a shorter daytime fasting period, for example, when exercising in the early evening after skipping lunch. However, it should not be forgotten that any physical activity (walking, housework, etc.), performed at any time of the day, is beneficial for health.