Childhood obesity, a ticking time bomb for cardiometabolic diseases

Childhood obesity, a ticking time bomb for cardiometabolic diseases

OVERVIEW

  • Obesity rates among Canadian children and teens have more than tripled over the past 40 years.
  • Childhood obesity is associated with a marked increase in the risk of type 2 diabetes and cardiovascular disease in adulthood, which can significantly reduce healthy life expectancy.
  • Policies to improve the diet of young people are key to reversing this trend and preventing an epidemic ofcardiometabolic diseases affecting young adults in the coming years.

One of the most dramatic changes to have occurred in recent years is undoubtedly the marked increase in the number of overweight children. For example, obesity rates among Canadian children and adolescents have more than tripled over the past 40 years. Whereas in 1975, obesity was a fairly rare problem affecting less than 3% of children aged 5–19, the prevalence of obesity has made a gigantic leap since that time, affecting nearly 14% of boys and 10% of girls in 2016 (Figure 1). If data on overweight is added to these figures, then approximately 25% of young Canadians are overweight (a similar trend is observed in Quebec). This prevalence of obesity appears to have plateaued in recent years, but recent US surveys suggest that the COVID-19 pandemic may have caused an upsurge in the number of overweight young people, particularly among 5-11-year-olds.

Figure 1. Increase in the prevalence of obesity among Canadian children over the past 40 years. From NCD Risk Factor Collaboration (2017).

Measuring childhood obesity
Although not perfect, the most common measure used to determine the presence of overweight in young people under the age of 19 is the body mass index (BMI), calculated by dividing the weight by the square of height (kg/m²). However, the values obtained must be adjusted according to age and sex to take into account changes in body composition during growth, as shown in Figure 2.

Figure 2. WHO growth standards for boys aged 5–19 living in Canada. Data comes from WHO (2007).

Note that a wide range of BMI on either side of the median (50th percentile) is considered normal. Overweight children have a BMI higher than that of 85–95% of the population of the same age (85th-95th percentile), while the BMI of obese children is higher than that of 97% of the population of the same age (97th percentile and above). Using z-scores is another way to visualize childhood overweight and obesity. This measurement expresses the deviation of the BMI from the mean value, in standard deviation. For example, a z-score of 1 means that the BMI is one standard deviation above normal (corresponding to overweight), while z-scores of 2 and 3 indicate, respectively, the presence of obesity and severe obesity.

This marked increase in the proportion of overweight children, and particularly obese children, is a worrying trend that bodes very badly for the health of future generations of adults. On the one hand, it is well established that obesity during childhood (and especially during adolescence) represents a very high risk factor for obesity in adulthood, with more than 80% of obese adults who were already obese during their childhood. This obesity in adulthood is associated with an increased risk of a host of health problems, both from a cardiovascular point of view (hypertension, dyslipidemia, ischemic diseases) and the development of metabolic abnormalities (hyperglycemia, resistance to insulin, type 2 diabetes) and certain types of cancer. Obesity can also cause discrimination and social stigma and therefore have devastating consequences on the quality of life, both physically and mentally.

Another very damaging aspect of childhood obesity, which is rarely mentioned, is the dramatic acceleration of the development of all the diseases associated with overweight. In other words, obese children are not only at higher risk of suffering from the various pathologies caused by obesity in adulthood, but these diseases can also affect them at an early age, sometimes even before reaching adulthood, and thus considerably reduce their healthy life expectancy. These early impacts of childhood obesity on the development of diseases associated with overweight are well illustrated by the results of several recent studies on type 2 diabetes and cardiovascular disease.

Early diabetes
Traditionally, type 2 diabetes was an extremely rare disease among young people (it was even called “adult diabetes” at one time), but its incidence has increased dramatically with the rise in the proportion of obese young people. For example, recent US statistics show that the prevalence of type 2 diabetes in children aged 10–19 has increased from 0.34 per 1000 children in 2001 to 0.67 in 2017, an increase of almost 100% since the beginning of the millennium.

The main risk factors for early diabetes are obesity, especially severe obesity (BMI greater than 35) or when the excess fat is mainly located in the abdomen, a family history of the disease, and belonging to certain ethnic groups. However, obesity remains the main risk factor for type 2 diabetes: in obese children (4–10 years) and adolescents (11–18 years), glucose intolerance is frequently observed during induced hyperglycemia tests, a phenomenon caused by the early development of insulin resistance. A characteristic of type 2 diabetes in young people is its rapid development. Whereas in adults, the transition from a prediabetic state to clearly defined diabetes is generally a gradual process, occurring over a period of 5–10 years, this transition can occur very quickly in young people, in less than 2 years. This means that the disease is much more aggressive in young people than in older people and can cause the early onset of various complications, particularly at the cardiovascular level.

A recent study, published in the prestigious New England Journal of Medicine, clearly illustrates the dangers that arise from early-onset type 2 diabetes, appearing during childhood or adolescence. In this study, the researchers recruited extremely obese children (BMI ≥ 35) who had been diagnosed with type 2 diabetes in adolescence and subsequently examined for ten years the evolution of different risk factors and pathologies associated with this disease.

The results are very worrying, because the vast majority of patients in the study developed one or more complications during follow-up that significantly increased their risk of developing serious health problems (Figure 3). Of particular note is the high incidence of hypertension, dyslipidemia (LDL-cholesterol and triglyceride levels too high), and kidney (nephropathies) and nerve damage (neuropathies) in this population, which, it should be remembered, is only 26 years on average. Worse still, almost a third of these young adults had 2 or more complications, which obviously increases the risk of deterioration of their health even more. Moreover, it should be noted that 17 serious cardiovascular accidents (infarction, heart failure, stroke) occurred during the follow-up period, which is abnormally high given the young age of the patients and the relatively small number of people who participated in the study (500 patients).

Figure 3. Incidence of different complications associated with type 2 diabetes in adolescents. From TODAY Study Group (2021).

It should also be noted that these complications occurred despite the fact that the majority of these patients were treated with antidiabetic drugs such as metformin or insulin. This is consistent with several studies showing that type 2 diabetes is much harder to control in young people than in middle-aged people. The mechanisms responsible for this difference are still poorly understood, but it seems that the development of insulin resistance and the deterioration of the pancreatic cells that produce this hormone progress much faster in young people than in older people, which complicates blood sugar control and increases the risk of complications.

This difficulty in effectively treating early type 2 diabetes means that young diabetics are much more at risk of dying prematurely than non-diabetics (Figure 4). For example, young people who develop early diabetes, before the age of 30, have a mortality rate 3 times higher than the population of the same age who is not diabetic. This increase remains significant, although less pronounced, until about age 50, while cases of diabetes that appear at older ages (60 years and over) do not have a major impact on mortality compared to the general population. It should be noted that this increase in mortality affecting the youngest diabetics is particularly pronounced at a young age, around 40 years of age.

These results therefore show how early type 2 diabetes can lead to a rapid deterioration in health and take decades off life, including years that are often considered the most productive of life (forties and fifties). For all these reasons, type 2 diabetes must be considered one of the main collateral damages of childhood obesity.

Figure 4. Age-standardized mortality rates for diagnosis of type 2 diabetes. Standardized mortality rates represent the ratio of mortality observed in individuals with diabetes to anticipated mortality for each age group. From Al-Saeed et al. (2016).

Cardiovascular disease
In recent years, there has been an upsurge in the incidence of cardiovascular disease in young adults. This new trend is surprising given that mortality from cardiovascular diseases has been in constant decline for several years in the general population (thanks in particular to a reduction in the number of smokers and improved treatments), and one might have expected that young people would also benefit from these positive developments.

The data collected so far strongly suggests that the increase in the prevalence of obesity among young people contributes to this upsurge of premature cardiovascular diseases, before the age of 55. On the one hand, it has been shown that a genetic predisposition to develop overweight during childhood is associated with an increased risk of coronary heart disease (and type 2 diabetes) in adulthood. On the other hand, this increased risk has also been observed in long-term studies examining the association between the weight of individuals during childhood and the incidence of cardiovascular events once they have reached adulthood. For example, a large Danish study of over 275,000 school-aged children (7–13 years old) showed that each one-unit increase in BMI z-score at these ages (see legend to Figure 2 for the definition of the z-score) was associated with an increased risk of cardiovascular disease in adulthood, after 25 years (Figure 5).

This increased risk is directly proportional to the age at which children are overweight, i.e., the more a high BMI is present at older ages, the greater the risk of suffering a cardiovascular event later in adulthood. For example, an increase of 1 in the z -score of 13-year-old children is associated with twice as much of an increase in risk in adulthood as a similar increase in a 7-year-old child (Figure 5). Similar results are observed for girls, but the increased risk of cardiovascular disease is lower than for boys.


Figure 5. Relationship between body mass index in childhood and the risk of cardiovascular disease in adulthood. The values represent the risks associated with a 1-unit increase in BMI z-score at each age. From Baker et al. (2007).

Early atherosclerosis
Several studies suggest that the increased risk of cardiovascular disease in adulthood observed in overweight children is a consequence of the early development of several risk factors that accelerate the process of atherosclerosis. Autopsy studies of obese adolescents who died of non-cardiovascular causes (e.g., accidents) revealed that fibrous atherosclerotic plaques were already present in the aorta and coronary arteries, indicating an abnormally rapid progression of atherosclerosis.

As mentioned earlier, type 2 diabetes is certainly the worst risk factor that can generate this premature progression, because the vast majority of diabetic children and adolescents very quickly develop several abnormalities that considerably increase the risk of serious damage to blood vessels (Figure 3). But even without the presence of early diabetes, studies show that several risk factors for cardiovascular disease are already present in overweight children, such as hypertension, dyslipidemia, chronic inflammation, glucose intolerance or even vascular abnormalities (thickening of the internal wall of the carotid artery, for example). Exposure to these factors that begins in childhood therefore creates favourable conditions for the premature development of atherosclerosis, thereby increasing the risk of cardiovascular events in adulthood.

It should be noted, however, that the negative impact of childhood obesity on health in adulthood is not irreversible. Indeed, studies show that people who were overweight or obese during childhood, but who had a normal weight in adulthood, have a risk of cardiovascular disease similar to that of people who have been thin all their lives. However, obesity is extremely difficult to treat, both in childhood and in adulthood, and the best way to avoid prolonged chronic exposure to excess fat and damage to cardiovascular health (and health in general) which results from it is obviously to prevent the problem at the source by modifying lifestyle factors, which are closely associated with an increased risk of developing overweight, in particular the nature of the diet and physical activity (psychosocial stress may also play a role). Given the catastrophic effects of childhood obesity on health, cardiovascular health in particular, the potential for this early preventive approach (called “primordial prevention”) is immense and could help halt the current rise in diabetes and premature mortality affecting young adults.

Ideal cardiovascular health
A recent study shows how this primordial prevention approach can have an extraordinary impact on cardiovascular health. In this study, researchers determined the ideal cardiovascular health score, as defined by the American Heart Association (Table 1), of more than 3 million South Koreans with an average age of 20–39 years. Excess weight is a very important element of this score because of its influence on other risk factors also used in the score such as hypertension, fasting hyperglycemia and cholesterol.

Participants were followed for a period of approximately 16 years, and the incidence of premature cardiovascular disease (before age 55) was assessed using as the primary endpoint a combination of hospitalization for infarction, stroke, cardiac insufficiency, or sudden cardiac death.

Table 1. Parameters used to define the ideal cardiovascular health score. Since there is 1 point for each target reached, a score of 6 reflects optimal cardiovascular health. Adapted from Lloyd-Jones et al. (2010), excluding dietary factors that were not assessed in the Korean study.

As shown in Figure 6, cardiovascular health in early adulthood has a decisive influence on the risk of cardiovascular events that occur prematurely, before the age of 55. Compared to participants in very poor cardiovascular health at the start (score of 0), each additional target reached reduces the risk of cardiovascular events, with maximum protection of approximately 85% in people whose lifestyle allows achieving 5 or more ideal heart health targets (scores of 5 and 6). Similar results were obtained in the United States and show how early health, from childhood through young adulthood, plays a key role in preventing the development of cardiovascular disease during aging.

Figure 6. Influence of cardiovascular health in young adults on the risk of premature cardiovascular events. From Lee et al. (2021).

Yet our society remains strangely passive in the face of the rise in childhood obesity, as if the increase in body weight of children and adolescents has become the norm and that nothing can be done to reverse this trend. This lack of interest is really difficult to understand, because the current situation is a ticking time bomb that risks causing a tsunami of premature chronic diseases in the near future, affecting young adults. This is an extremely worrying scenario if we consider that our healthcare system, in addition to having to contend with diseases that affect an aging population (1 out of 4 Quebecers will be over 65 in 2030), will also have to deal with younger patients suffering from cardiometabolic diseases caused by overweight. Needless to say, this will be a significant burden on healthcare systems.

This situation is not inevitable, however, as governments have concrete legislative means that can be used to try to reverse this trend. Several policies aimed at improving diet quality to prevent disease can be quickly implemented:

  • Taxing sugary drinks. A simple and straightforward approach that has been adopted by several countries is to introduce a tax on industrial food products, especially soft drinks. The principle is the same as for all taxes affecting other products harmful to health such as alcohol and tobacco, i.e., an increase in prices is generally associated with a reduction in consumption. Studies that have examined the impact of this approach for soft drinks indicate that this is indeed the case, with reductions in consumption observed (among others) in Mexico, Berkeley (California) and Barbados. This approach therefore represents a promising tool, especially if the amounts collected are reinvested in order to improve the diet of the population (subsidies for the purchase of fruit and vegetables, for example).
  • Requiring clear nutrition labels on packaging. We can help consumers make informed choices by clearly indicating on the front of the product whether it is high in sugar, fat or salt, as is the case in Chile (see our article on this subject).
  • Eliminating the marketing of unhealthy foods for children. The example of Chile also shows that severe restrictions can be imposed on the marketing of junk food products by prohibiting the advertising of these products in programs or websites aimed at young people as well as by prohibiting their sale in schools. The United Kingdom plans to take such an approach very soon by eliminating all advertising online and on television of products high in sugar, salt and fat before 9 p.m., while Mexico has gone even further by banning all sales of junk food products to children.

There is no reason Canada should not adopt such approaches to protect the health of young people.

Lignans: Compounds of plant origin that promote good cardiovascular health

Lignans: Compounds of plant origin that promote good cardiovascular health

OVERVIEW

  • Dietary lignans are phenolic compounds that come mainly from plant-based foods, especially seeds, whole grains, fruits, vegetables, wine, tea and coffee.
  • Consumption of lignans is associated with a reduced risk of developing cardiovascular disease, according to several well-conducted studies.

There are over 8,000 phenolic and polyphenolic compounds found in plants. These compounds are not nutrients, but they have various beneficial biological activities in the human body. They are generally grouped into 4 classes: phenolic acids, flavonoids, stilbenes (e.g., resveratrol), and lignans. Lignans are dimers of monolignols, which can also be used in the synthesis of a long branched polymer, lignin, found in the walls of the conductive vessels of plants. From a nutritional standpoint, lignins are considered to be a component of insoluble dietary fibre.

Figure 1. Structures of the main dietary lignans

Dietary lignans, the most important of which are matairesinol, secoisolariciresinol, pinoresinol and lariciresinol, come mainly from plant-based foods, particularly seeds, whole grains, fruits, vegetables, wine, tea and coffee (see Table 1). Other lignans are found only in certain types of food, such as medioresinol (sesame seeds, rye, lemon), syringaresinol (grains), sesamin (sesame seeds). Lignans are converted into enterolignans by the gut microbiota, which are then absorbed into the bloodstream and distributed throughout the body.

Table 1. Lignan content of commonly consumed foods.
Adapted from Peterson et al., 2010 and Rodriguez-Garcia et al., 2019.

Several studies indicate that lignans can prevent cardiovascular disease and other chronic diseases, including cancer, and improve cardiovascular health, through its anti-inflammatory and estrogenic properties (the ability to bind to estrogen receptors).

A recently published US study indicates that there is a significant association between dietary intake of lignans and the incidence of coronary heart disease. Among the 214,108 people from 3 cohorts of healthcare professionals, those who consumed the most lignans (total) had a 15% lower risk of developing coronary heart disease than those who consumed little. Considering each lignan separately, the association was particularly favourable for matairesinol (-24%), compared to secoisolariciresinol (-13%), pinoresinol (-11%), and lariciresinol (-11%). There is a nonlinear dose-response relationship for total lignans, matairesinol, and secoisolariciresinol with a plateau (maximum effect) at approximately 300 µg/day, 10 µg/day, and 100 µg/day, respectively. Canadians consume an average of 857 µg of lignans per day, enough to benefit from the positive effects on cardiovascular health, but residents of some Western countries such as the United Kingdom, the United States and Germany do not have an optimal intake of lignans (Table 2).

The favourable association for lignans was especially apparent among participants who had a high dietary fibre intake. The authors of the study suggest that fibre, by supporting a healthy microbiota, may promote the production of enterolignans in the gut.

Table 2. Daily intake of lignans in Western countries.
Adapted from Peterson et al., 2010.

PREDIMED (Prevención con Dieta Mediterránea), a recognized study conducted among over 7,000 Spaniards (55–80 years old) at high risk of developing cardiovascular disease, compared the Mediterranean diet (supplemented with nuts and extra virgin olive) to a low-fat diet advocated by the American Heart Association for the prevention of cardiovascular disease (CVD). In this study, the Mediterranean diet was clearly superior to the low-fat diet in preventing CVD, so the study was stopped after 4.8 years for ethical reasons. Further analysis of the PREDIMED data showed that there is a very favourable association between a high dietary intake of polyphenols and the risk of CVD. Participants who consumed the most total polyphenols had a 46% lower risk of CVD than those who consumed the least. The polyphenols that were most strongly associated with reduced risk of CVD were flavanols (-60%), hydroxybenzoic acids (-53%), and lignans (-49%). It should be noted that the nuts and extra virgin olive oil that were consumed daily by participants in the PREDIMED study contain appreciable amounts of lignans.

Another analysis  of data from the PREDIMED study showed a favourable association between total polyphenol intake and the risk of death from any cause. A high intake of total polyphenols, compared to a low intake, was associated with a 37% reduction in the risk of premature mortality. Stilbenes and lignans were the most favourable polyphenols for reducing the risk of mortality, by 52% and 40%, respectively. In this case, flavonoids and phenolic acids were not associated with a significant reduction in mortality risk.

No randomized controlled studies on phenolic compounds and the risk of CVD have been performed to date. There is therefore no direct evidence that lignans protect the cardiovascular system, but all the data from population studies suggests that it is beneficial for health to increase the dietary intake of lignans and therefore to eat more fruits, vegetables, whole grains, legumes, nuts and extra virgin olive oil, which are excellent sources of these still too little known plant-based compounds.

Choosing the right sources of carbohydrates is essential for preventing cardiovascular disease

Choosing the right sources of carbohydrates is essential for preventing cardiovascular disease

OVERVIEW

  • Recent studies show that people who regularly consume foods containing low-quality carbohydrates (simple sugars, refined flours) have an increased risk of cardiovascular events and premature mortality.
  • Conversely, a high dietary intake of complex carbohydrates, such as resistant starches and dietary fibre, is associated with a lower risk of cardiovascular disease and improved overall health.
  • Favouring the regular consumption of foods rich in complex carbohydrates (whole grains, legumes, nuts, fruits and vegetables) while reducing that of foods containing simple carbohydrates (processed foods, sugary drinks, etc.) is therefore a simple way to improve cardiovascular health.

It is now well established that a good quality diet is essential for the prevention of cardiovascular disease and the maintenance of good health in general. This link is particularly well documented with regard to dietary fat: several epidemiological studies have indeed reported that too high a dietary intake of saturated fat increases LDL cholesterol levels, an important contributor to the development of atherosclerosis, and is associated with an increased risk of cardiovascular disease. As a result, most experts agree that we should limit the intake of foods containing significant amounts of saturated fat, such as red meat, and instead focus on sources of unsaturated fat, such as vegetable oils (especially extra virgin olive oil and those rich in omega-3s such as canola), as well as nuts, certain seeds (flax, chia, hemp) and fish (see our article on this subject). This roughly corresponds to the Mediterranean diet, a diet that has repeatedly been associated with a lower risk of several chronic diseases, especially cardiovascular disease.

On the carbohydrate side, the consensus that has emerged in recent years is to favour sources of complex carbohydrates such as whole grains, legumes and plants in general while reducing the intake of simple carbohydrates from refined flour and added sugars. Following this recommendation, however, can be much more difficult than one might think, as many available food products contain these low-quality carbohydrates, especially the entire range of ultra-processed products, which account for almost half of the calories consumed by the population. It is therefore very important to learn to distinguish between good and bad carbohydrates, especially since these nutrients are the main source of calories consumed daily by the majority of people. To achieve this, we believe it is useful to recall where carbohydrates come from and how industrial processing of foods can affect their properties and impacts on health.

Sugar polymers
All of the carbohydrates in our diet come from, in one way or another, plants. During the photosynthetic reaction, in addition to forming oxygen (O2) from carbon dioxide in the air (CO2), plants also simultaneously transform the energy contained in solar radiation into chemical energy, in the form of sugar:

6 CO2 + 12 H2O + light → C6H12O6 (glucose) + 6 O2 + 6 H2O

In the vast majority of cases, this sugar made by plants does not remain in this simple sugar form, but is rather used to make complex polymers, i.e., chains containing several hundred (and in some cases thousands) sugar molecules chemically bonded to one another. An important consequence of this arrangement is that the sugar contained in these complex carbohydrates is not immediately accessible and must be extracted by digestion before reaching the bloodstream and serving as a source of energy for the body’s cells. This prerequisite helps prevent sugar from entering the blood too rapidly, which would unbalance the control systems responsible for maintaining the concentration of this molecule at levels just sufficient enough to meet the needs of the body. And these levels are much lower than one might think; on average, the blood of a healthy person contains a maximum of 4 to 5 g of sugar in total, or barely the equivalent of a teaspoon. Dietary intake of complex carbohydrates therefore provides enough energy to support our metabolism, while avoiding excessive fluctuations in blood sugar that could lead to health problems.

Figure 1 illustrates the distribution of the two main types of sugar polymers in the plant cell: starches and fibres.

Figure 1. The physicochemical characteristics and physiological impacts of starches and dietary fibres from plant cells. Adapted from Gill et al. (2021).

Starches. Starches are glucose polymers that the plant stores as an energy reserve in granules (amyloplasts) located inside plant cells. This source of dietary carbohydrates has been part of the human diet since the dawn of time, as evidenced by the recent discovery of genes from bacteria specializing in the digestion of starches in the dental plaque of individuals of the genus Homo who lived more than 100,000 years ago. Even today, a very large number of plants commonly eaten are rich in starch, in particular tubers (potatoes, etc.), cereals (wheat, rice, barley, corn, etc.), pseudocereals (quinoa, chia, etc.), legumes, and fruits.

Digestion of the starches present in these plants releases units of glucose into the bloodstream and thus provides the energy necessary to support cell metabolism. However, several factors can influence the degree and speed of digestion of these starches (and the resulting rise in blood sugar). This is particularly the case with “resistant starches” which are not at all (or very little) digested during gastrointestinal transit and therefore remain intact until they reach the colon. Depending on the factors responsible for their resistance to digestion, three main types of these resistant starches (RS) can be identified:

  • RS-1: These starches are physically inaccessible for digestion because they are trapped inside unbroken plant cells, such as whole grains.
  • RS-2: The sensitivity of starches to digestion can also vary considerably depending on the source and the degree of organization of the glucose chains within the granules. For example, the most common form of starch in the plant kingdom is amylopectin (70–80% of total starch), a polymer made up of several branches of glucose chains. This branched structure increases the contact surface with enzymes specialized in the digestion of starches (amylases) and allows better extraction of the glucose units present in the polymer. The other constituent of starch, amylose, has a much more linear structure which reduces the efficiency of enzymes to extract the glucose present in the polymer. As a result, foods with a higher proportion of amylose are more resistant to breakdown, release less glucose, and therefore cause lower blood sugar levels. This is the case, for example, with legumes, which contain up to 50% of their starch in the form of amylose, which is much more than other commonly consumed sources of starches, such as tubers and grains.
  • RS-3: These resistant starches are formed when starch granules are heated and subsequently cooled. The resulting starch crystallization, a phenomenon called retrogradation, creates a rigid structure that protects the starch from digestive enzymes. Pasta salads, potato salads, and sushi rice are all examples of foods containing resistant starches of this type.

An immediate consequence of this resistance of digestion-resistant starches is that these glucose polymers can be considered dietary fibre from a functional point of view. This is important because, as discussed below, the fermentation of fibre by the hundreds of billions of bacteria (microbiota) present in the colon generates several metabolites that play extremely important roles in the maintenance of good health.

Dietary fibre. Fibres are polymers of glucose present in large quantities in the wall of plant cells where they play an important role in maintaining the structure and rigidity of plants. The structure of these fibres makes them completely resistant to digestion and the sugar they contain does not contribute to energy supply. Traditionally, there are two main types of dietary fibre, soluble and insoluble, each with its own physicochemical properties and physiological effects. Everyone has heard of insoluble fibre (in wheat bran, for example), which increases stool volume and speeds up gastrointestinal transit (the famous “regularity”). This mechanical role of insoluble fibres is important, but from a physiological point of view, it is mainly soluble fibres that deserve special attention because of the many positive effects they have on health.

By capturing water, these soluble fibres increase the viscosity of the digestive contents, which helps to reduce the absorption of sugar and dietary fats and thus to avoid excessive increases in blood sugar and blood lipid levels that can contribute to atherosclerosis (LDL cholesterol, triglycerides). The presence of soluble fibre also slows down gastric emptying and can therefore decrease calorie intake by increasing feelings of satiety. Finally, the bacterial community that resides in the colon (the microbiota) loves soluble fibres (and resistant starches), and this bacterial fermentation generates several bioactive substances, in particular the short chain fatty acids (SCFA) acetate, propionate and butyrate. Several studies carried out in recent years have shown that these molecules exert a myriad of positive effects on the body, whether by reducing chronic inflammation, improving insulin resistance, lowering blood pressure and the risk of cardiovascular disease, or promoting the establishment of a diversified microbiota, optimal for colon health (Table 1).

A compilation of many studies carried out in recent years (185 observational studies and 58 randomized trials, which equates to 135 million person-years) indicates that consuming 25 to 30 g of fibre per day seems optimal to benefit from these protective effects, approximately double the current average consumption.

Table 1. Main physiological effects of dietary fibre. Adapted from Barber (2020).

Physiological effectsBeneficial health impacts
MetabolismImproved insulin sensitivity
Reduced risk of type 2 diabetes
Improved blood sugar and lipid profile
Body weight control
Gut microbiotaPromotes a diversified microbiota
Production of short-chain fatty acids
Cardiovascular systemDecrease in chronic inflammation
Reduced risk of cardiovascular events
Reduction of cardiovascular mortality
Digestive systemDecreased risk of colorectal cancer

Overall, we can therefore see that the consumption of complex carbohydrates is optimal for our metabolism, not only because it ensures an adequate supply of energy in the form of sugar, without causing large fluctuations in blood sugar, but also because it provides the intestinal microbiota with the elements necessary for the production of metabolites essential for the prevention of several chronic diseases and for the maintenance of good health in general.

Modern sugars
The situation is quite different, however, for several sources of carbohydrates in modern diets, especially those found in processed industrial foods. Three main problems are associated with processing:

Simple sugars. Simple sugars (glucose, fructose, galactose, etc.) are the molecules responsible for the sweet taste: the interaction of these sugars with receptors present in the tongue sends a signal to the brain warning it of the presence of an energy source. The brain, which alone consumes no less than 120 g of sugar per day, loves sugar and responds positively to this information, which explains our innate attraction to foods with a sweet taste. On the other hand, since the vast majority of carbohydrates produced by plants are in the form of polymers (starches and fibres), simple sugars are actually quite rare in nature, being mainly found in fruits, vegetables such as beets, or even some grasses (sugar cane). It is therefore only with the industrial production of sugar from sugar cane and beets that consumers’ “sweet tooth” could be satisfied on a large scale and that simple sugars became commonly consumed. For example, data collected in the United States shows that between 1820 and 2016, the intake of simple sugars increased from 6 lb (2.7 kg) to 95 lb (43 kg) per person per year, an increase of about 15 times in just under 200 years (Figure 2).

 

 

Figure 2. Consumption of simple sugars in the United States between 1820 and 2016.  From Guyenet (2018).

Our metabolism is obviously not adapted to this very high intake of simple sugars, far beyond what is normally found in nature. Unlike the sugars found in complex carbohydrates, these simple sugars are absorbed very quickly into the bloodstream and cause very rapid and significant increases in blood sugar. Several studies have shown that people who frequently consume foods containing these simple sugars are more likely to suffer from obesity, type 2 diabetes and cardiovascular disease. For example, studies have found that consuming 2 servings of sugary drinks daily was associated with a 35% increase in the risk of coronary heart disease. When the amount of added sugars consumed represents 25% of daily calories, the risk of heart disease nearly triples. Factors that contribute to this detrimental effect of simple sugars on cardiovascular health include increased blood pressure and triglyceride levels, lowered HDL cholesterol, and increased LDL cholesterol (specifically small, very dense LDLs, which are more harmful to the arteries), as well as an increase in inflammation and oxidative stress.

It is therefore necessary to restrict as much as possible the intake of simple sugars, which should not exceed 10% of the daily energy intake according to the World Health Organization. For the average adult who consumes 2,000 calories per day, that’s just 200 calories, or about 12 teaspoons of sugar or the equivalent of a single can of soft drink.

Refined flour.  Cereals are a major source of carbohydrates (and calories) in most food cultures around the world. When they are in whole form, i.e., they retain the outer shell rich in fibre and the germ containing several vitamins and minerals, cereals are a source of complex carbohydrates (starches) of high quality and beneficial to health. This positive impact of whole grains is well illustrated by the reduced risk of coronary heart disease and mortality observed in a large number of population studies. For example, recent meta-analyses have shown that the consumption of about 50 g of whole grains perday is associated with a 22–30% reduction in cardiovascular disease mortality, a 14–18% reduction in cancer-relatedmortality, and a 19–22% reduction in total mortality.

On the other hand, these positive effects are completely eliminated when the grains are refined with modern industrial metal mills to produce the flour used in the manufacture of a very large number of commonly consumed products (breads, pastries, pasta, desserts, etc.). By removing the outer shell of the grain and its germ, this process improves the texture and shelf life of the flour (the unsaturated fatty acids in the germ are sensitive to rancidity), but at the cost of the almost total elimination of fibres and a marked depletion of several nutrients (minerals, vitamins, unsaturated fatty acids, etc.). Refined flours therefore essentially only contain sugar in the form of starch, this sugar being much easier to assimilate due to the absence of fibres that normally slow down the digestion of starch and the absorption of released sugar (Figure 3).

Figure 3. Schematic representation of a whole and refined grain of wheat.

Fibre deficiency. Fortification processes partially compensate for the losses of certain nutrients (e.g., folic acid) that occur during the refining of cereal grains. On the other hand, the loss of fibre during grain refining is irreversible and is directly responsible for one of the most serious modern dietary deficiencies given the many positive effects of fibre on the prevention of several chronic diseases.

Poor-quality carbohydrates
Low-quality carbohydrate sources with a negative impact on health are therefore foods containing a high amount of simple sugars, having a higher content of refined grains than whole grains, or containing a low amount of fibre (or several of these characteristics simultaneously). A common way to describe these poor-quality carbohydrates is to compare the rise in blood sugar they produce to that of pure glucose, called the glycemic index (GI) (see box). The consumption of food with a high glycemic index causes a rapid and dramatic rise in blood sugar levels, which causes the pancreas to secrete a large amount of insulin to get glucose into the cells. This hyperinsulinemia can cause glucose to drop to too low levels, and the resulting hypoglycemia can ironically stimulate appetite, despite ingesting a large amount of sugar a few hours earlier. Conversely, a food with a low glycemic index produces lower, but sustained, blood sugar levels, which reduces the demand for insulin and helps prevent the fluctuations in blood glucose levels often seen with foods with a high glycemic index. Potatoes, breakfast cereals, white bread, and pastries are all examples of high glycemic index foods, while legumes, vegetables, and nuts are conversely foods with a low glycemic index.

Glycemic index and load
The glycemic index (GI) is calculated by comparing the increase in blood sugar levels produced by the absorption of a given food with that of pure glucose. For example, a food that has a glycemic index of 50 (lentils, for example) produces a blood sugar half as important as glucose (which has a glycemic index of 100). As a general rule, values below 50 are considered to correspond to a low GI, while those above 70 are considered high. The glycemic index, however, does not take into account the amount of carbohydrate in foods, so it is often more appropriate to use the concept of glycemic load (GL). For example, although watermelon and breakfast cereals both have high GIs (75), the low-carbohydrate content of melon (11 g per 100 g) equates to a glycemic load of 8, while 26 g of carbohydrates present in breakfast cereals result in a load of 22, which is three times more. GLs ≥ 20 are considered high, intermediate when between 11 and 19, and low when ≤ 10.

PURE study
Results from the PURE (Prospective Urban and Rural Epidemiology) epidemiological study conducted by Canadian cardiologist Salim Yusuf have confirmed the link between low-quality carbohydrates and the risk of cardiovascular disease. In the first of these studies, published in the prestigious New England Journal of Medicine, researchers examined the association between the glycemic index and the total glycemic load of the diet and the incidence of major cardiovascular events (heart attack, stroke, sudden death, heart failure) in more than 130,000 participants aged 35 to 70, spread across all five continents. The study finds that a diet with a high glycemic index is associated with a significant (25%) increase in the risk of having a major cardiovascular event in people without cardiovascular disease, an increase that reaches 51% in those with pre-existing cardiovascular disease (Figure 4). A similar trend is observed for the glycemic load, but in the latter case, the increased risk seems to affect only those with cardiovascular disease at the start of the study.

Figure 4. Comparison of the risk of cardiovascular events according to the glycemic index or the glycemic load of the diet of healthy people (blue) or with a history of cardiovascular disease (red). The median glycemic index values were 76 for quintile 1 and 91 for quintile 5. For glycemic load, the mean values were 136 g of carbohydrates per day for Q1 and 468 g per day for Q5. Note that the increased risk of cardiovascular events associated with a high glycemic index or load is primarily seen in participants with pre-existing cardiovascular disease. From Jenkins et al. (2021).

The impact of the glycemic index appears to be particularly pronounced in overweight people (Figure 5). Thus, while the increase in the risk of major cardiovascular events is 14% in thin people with a BMI less than 25, it reaches 38% in those who are overweight (BMI over 25).

 

Figure 5. Impact of overweight on the increased risk of cardiovascular events related to the glycemic index of the diet. The values shown represent the increased risk of cardiovascular events observed for each category (quintiles 2 to 5) of the glycemic index compared to the category with the lowest index (quintile 1). The median values of the glycemic indices were 76 for quintile 1; 81 for quintile 2; 86 for quintile 3; 89 for quintile 4; and 91 for quintile 5. Taken from Jenkins et al. (2021).

This result is not so surprising, since it has long been known that excess fat disrupts sugar metabolism, especially by producing insulin resistance. A diet with a high glycemic index therefore exacerbates the rise in postprandial blood sugar already in place due to excess weight, which leads to a greater increase in the risk of cardiovascular disease. The message to be drawn from this study is therefore very clear: a diet containing too many easily assimilated sugars, as measured using the glycemic index, is associated with a significant increase in the risk of suffering a major cardiovascular event. The risk of these events is particularly pronounced for people with less than optimal health, either due to the presence of excess fat or pre-existing cardiovascular disease (or both). Reducing the glycemic index of the diet by consuming more foods containing complex carbohydrates (fruits, vegetables, legumes, nuts) and fewer products containing added sugars or refined flour is therefore an essential prerequisite for preventing the development of cardiovascular disease.

Refined flours
Another part of the PURE study looked more specifically at refined flours as a source of easily assimilated sugars that can abnormally increase blood sugar levels and increase the risk of cardiovascular disease. Researchers observed that a high intake (350 g per day, or 7 servings) of products containing refined flours (white bread, breakfast cereals, cookies, crackers, pastries) was associated with a 33% increase in the risk of coronary heart disease, 47% in the risk of stroke, and 27% in the risk of premature death. These observations therefore confirm the negative impact of refined flours on health and the importance of including as much as possible foods containing whole grains in the diet. The preventive potential of this simple dietary change is enormous since the consumption of whole grains remains extremely low, with the majority of the population of industrialized countries consuming less than 1 serving of whole grains daily, well below the recommended minimum (half of all grain products consumed, or about 5 servings per day).

Wholemeal breads are still a great way to boost the whole-grain intake. However, special attention must be paid to the list of ingredients. In Canada, the law allows up to 5% of the grain to be removed when making whole wheat flour, and the part removed contains most of the germ and a fraction of the bran (fibres). This type of bread is superior to white bread, but it is preferable to choose products made from whole-grain flour which contains all the parts of the grain. Note also that multigrain breads (7-14 grains) always contain 80% wheat flour and a maximum of 20% of a mixture of other grains (otherwise the bread does not rise), so the number of grains does not matter, but what does matter is whether the flour is whole wheat or ideally integral, which is not always the case.

In short, a simple way to reduce the risk of cardiovascular events and improve health in general is to replace as much as possible the intake of foods rich in simple sugars and refined flour with plant-based foods containing complex carbohydrates. In addition to carbohydrates, this simple change alone will influence the nature of the proteins and lipids ingested as well as, at the same time, all the phenomena that promote the appearance and progression of atherosclerotic plaques.

Omega-3 fatty acid supplements are ineffective for the prevention of cardiovascular disease

Omega-3 fatty acid supplements are ineffective for the prevention of cardiovascular disease

OVERVIEW

  • The VITAL study in participants who did not have cardiovascular disease and the ASCEND study in diabetic patients did not show a beneficial effect of omega-3 fatty acid supplements on cardiovascular health.
  • The REDUCE-IT study reported a beneficial effect of an omega-3 fatty acid supplement (Vascepa®), while the STRENGTH study reported no effect of another supplement (Epanova®).
  • The divergent results of the REDUCE-IT and STRENGTH studies have raised scientific controversy, mainly about the questionable use of mineral oil as a neutral placebo in the REDUCE-IT study.
  • Overall, the results of the studies lead to the conclusion that omega-3 fatty acid supplements are ineffective in preventing cardiovascular disease, in primary prevention and most likely also in secondary prevention.

Consuming fish on a regular basis (1–2 times per week) is associated with a reduced risk of death from coronary heart disease (see these meta-analyses here and here). In addition, favourable associations between fish consumption and the risks of type 2 diabetes, stroke, dementia, Alzheimer’s disease and cognitive decline have also been identified.

A large number of studies have suggested that it is mainly omega-3 (O-3) fatty acids, a type of very long-chain polyunsaturated fatty acid found in high amounts in several fish species, that are the cause of the positive health effects of eating fish and other seafood. For example, a meta-analysis of 17 prospective studies published in 2021 indicates that the risk of dying prematurely was significantly lower (15–18%) in participants who had the most circulating O-3s, compared to those who had the least. In addition, favourable associations of the same magnitude were observed for cardiovascular and cancer-related mortality.

Since eating fish is associated with better cardiovascular health, why not isolate the “active ingredient”, i.e. the omega-3 fatty acids it contains and make supplements with them? This seemed like a great idea; the same pharmacological approach has been applied successfully to a host of plants, fungi and microorganisms, which has made it possible to create drugs. One such example is aspirin, a derivative of salicylic acid found in the bark of certain tree species, quinine extracted from the cinchona shrub (antimalarial), digitoxin extracted from purple digitalis (treatment of heart problems), paclitaxel from yew (anticancer), etc.

Are marine O-3 supplements just as or even more effective than the whole food from which they are extracted? Several randomized controlled studies (RCTs) have been carried out in recent years to try to prove the effectiveness of O-3s. Meta-analyses of RCTs (see here and here) indicate that O-3 supplements (EPA and DHA) have little or no effect in primary prevention, i.e. on the risk of developing cardiovascular disease or dying prematurely from cardiovascular disease or any other cause. In contrast, data from some studies indicated that O-3 supplements may have beneficial effects in secondary prevention, i.e. in people with cardiovascular disease.

In order to obtain a higher level of evidence, several large, well-planned and controlled studies have been carried out recently: ASCEND, VITAL, STRENGTH and REDUCE-IT. The VITAL study (VITamin D and omegA-3 TriaL) in 25,871 participants who did not have cardiovascular disease and the ASCEND study (A Study of Cardiovascular Events in Diabetes) in 15,480 diabetic patients did not demonstrate any beneficial effects of O-3 supplements on cardiovascular health.

The results of the REDUCE-IT (REDUction of Cardiovascular Events with Icosapent ethyl-Intervention Trial) and STRENGTH (Outcomes Study to Assess STatin Residual Risk Reduction With EpaNova in HiGh CV Risk PatienTs With Hypertriglyceridemia) studies were then published. The results of these studies were eagerly anticipated since they tested the effect of O-3 supplements on major strokes at high doses (3000–4000 mg O-3/day) in patients at risk treated with a statin to lower blood cholesterol, but who had high triglyceride levels.

The results of these two studies are divergent, which has raised scientific controversy. The REDUCE-IT study reported a significant reduction of 25% in the number of cardiovascular events in the group of patients who took daily O-3 supplementation (Vascepa®; ethyl-EPA), compared to the group of patients who took a placebo (mineral oil). The STRENGTH study reported an absence of effect of O-3 supplements (Epanova®; a mixture of EPA and DHA in the form of carboxylic acids) on major cardiovascular events in patients treated with a statin, compared to the group of patients who took a corn oil placebo.

Several hypotheses have been proposed to explain the different results between the two large studies. One of them is that the mineral oil used as a placebo in the REDUCE-IT study may have caused adverse effects that would have led to a false positive effect of the O-3 supplement. Indeed, mineral oil is not a neutral placebo since it caused an average increase of 37% of C-reactive protein (CRP), a marker of systemic inflammation in the control group, as well as a 7.4% increase in LDL cholesterol and 6.7% in apolipoprotein B compared to the group that took Vascepa. These three biomarkers are associated with an increased risk of cardiovascular events.

Two other hypotheses could explain the difference between the two studies. It is possible that the moderately higher plasma levels of EPA obtained in the REDUCE-IT study could be the cause of the beneficial effects seen in this study, or that the DHA used in combination with EPA in the STRENGTH study may have counteracted the beneficial effects of EPA.

To test these two hypotheses, the researchers responsible for the STRENGTH study performed post-hoc analyses of the data collected during their clinical trial. Patients were classified according to their plasma EPA level after 12 months of daily supplementation with O-3. Thus, in the first tertile, patients had an average plasma EPA concentration of 30 µg/mL, those in the second tertile: 90 µg/mL, and those in the third tertile: 151 µg/mL. The mean plasma concentration of EPA in the third tertile (151 µg/mL) is comparable to that reported in the REDUCE-IT study (144 µg/mL). Analyses show that there was no association between the plasma concentration of EPA or DHA and the number of major cardiovascular events. The authors conclude that there is no benefit to taking O-3 supplements for secondary prevention, but they suggest that more studies should be done in the future to compare mineral oil and corn oil as placebos and also to compare different formulations of omega-3 fatty acids.

Overall, the results of recent studies lead to the conclusion that O-3 supplements are ineffective in preventing cardiovascular disease, in primary prevention and most likely also in secondary prevention. It should be noted that, taken in large amounts, O-3 supplements can have unwanted effects. In fact, in both the STRENGTH and REDUCE-IT studies, the incidence of atrial fibrillation was significantly higher with the use of O-3 supplements. In addition, bleeding was more common in patients who took ethyl-EPA (Vascepa®) in the REDUCE-IT study than in patients who took the placebo. It therefore seems safer to eat fish once or twice a week to maintain good health than to take ineffective and expensive supplements.

Reducing calorie intake by eating more plants

Reducing calorie intake by eating more plants

OVERVIEW

  • Twenty volunteers were fed a low-fat or low-carbohydrate diet in turn for two weeks.
  • Participants on the low-fat diet consumed an average of nearly 700 fewer calories per day than with the low-carbohydrate diet, a decrease correlated with a greater loss of body fat.
  • Compared to the low-carbohydrate diet, the low-fat diet also led to lower cholesterol levels, reduced chronic inflammation, and lowered heart rate and blood pressure.
  • Overall, these results suggest that a diet mainly composed of plants and low in fat is optimal for cardiovascular health, both for its superiority in reducing calorie intake and for its positive impact on several risk factors for cardiovascular disease.

It is estimated that there are currently around 2 billion overweight people in the world, including 600 million who are obese. These statistics are truly alarming because it is clearly established that excess fat promotes the development of several diseases that decrease healthy life expectancy, including cardiovascular disease, type 2 diabetes, and several types of cancer. Identifying the factors responsible for this high prevalence of overweight and the possible ways to reverse this trend as quickly as possible is therefore essential to improve the health of the population and avoid unsustainable pressures on public health systems in the near future.

Energy imbalance
The root cause of overweight, and obesity in particular, is a calorie intake that exceeds the body’s energy needs. To lose weight, therefore, it is essentially a matter of restoring the balance between the calories ingested and the calories expended.

It might seem simple in theory, but in practice most people find it extremely difficult to lose weight. On the one hand, it is much easier to gain weight than to lose weight. During evolution, we have had to deal with periods of prolonged food shortages (and even starvation, in some cases) and our metabolism has adapted to these deficiencies by becoming extremely efficient at accumulating and conserving energy in the form of fat. On the other hand, the environment in which we currently live strongly encourages overconsumption of food. We are literally overwhelmed by an endless variety of attractive food products, which are often inexpensive, easily accessible, and promoted by very aggressive marketing that encourages their consumption. The current epidemic of overweight and obesity thus reflects our biological predisposition to accumulate reserves in the form of fat, a predisposition that is exacerbated by the obesogenic environment that surrounds us.

Eating less to restore balance
The body’s innate tendency to keep energy stored in reserve as fat makes it extremely difficult to lose weight by “burning” those excess calories by increasing the level of physical activity. For example, a person who eats a simple piece of sugar pie (400 calories) will have to walk about 6.5 km to completely burn off those calories, which, of course, is difficult to do on a daily basis. This does not mean that exercise is completely useless for weight loss. Research in recent years shows that exercise can specifically target certain fat stores, especially in the abdominal area. Studies also show that regular physical activity is very important for long-term maintenance of the weight lost from a low-calorie diet. However, there is no doubt that it is first and foremost the calories consumed that are the determining factors in weight gain. Moreover, contrary to what one might think, levels of physical activity have hardly changed for the last thirty years in industrialized countries, and the phenomenal increase in the number of overweight people is therefore mainly a consequence of overconsumption of food. Exercise is essential for the prevention of all chronic diseases and for the maintenance of general good health, but its role in weight loss is relatively minor. For overweight people, the only realistic way to lose weight significantly, and especially to maintain these losses over prolonged periods, is thus to reduce calorie intake.

Less sugar or less fat?
How do we get there? First, it’s important to realize that the surge in the number of overweight people has coincided with a greater availability of foods high in sugar or fat (and sometimes both). All countries in the world, without exception, that have adopted this type of diet have seen their overweight rates skyrocket, so it is likely that this change in eating habits plays a major role in the current obesity epidemic.

However, the respective contributions of sugar and fat to this increase in caloric intake and overweight are still the subjectof vigorous debate:

1) On the one hand, it has been proposed that foods high in fat are particularly obesogenic, since fats are twice as high in calories as carbohydrates, are less effective in causing a feeling of satiety, and improve the organoleptic properties of foods, which generally encourages (often unconscious) overconsumption of food. Therefore, the best way to avoid overeating and becoming overweight would be to reduce the total fat intake (especially saturated fat due to its negative impact on LDL-cholesterol levels) and replace it with complex carbohydrates (vegetables, legumes, whole-grain cereals). This is colloquially called the low-fat approach, advocated for example by the Ornish diet.

2) On the other hand, the exact opposite is proposed, i.e. that it would be mainly carbohydrates that would contribute to overconsumption of food and to the increase in the incidence of obesity. According to this model, carbohydrates in foods in the form of free sugars or refined flours cause insulin levels to rise markedly, causing massive energy storage in adipose tissue. As a result, fewer calories remain available in the circulation for use by the rest of the body, causing increased appetite and overeating to compensate for this lack. In other words, it wouldn’t be because we eat too much that we get fat, but rather because we are too fat we eat too much.

3) By preventing excessive fluctuations in insulin levels, a diet low in carbohydrates would thus limit the anabolic effect of this hormone and, therefore, prevent overeating and the accumulation of excess fat.

Less fat on the menu, fewer calories ingested
To compare the impact of low-carb and low-fat diets on calorie intake, Dr. Kevin Hall’s group (NIH) recruited 20 volunteers who were fed each of these diets in turn for two weeks. The strength of this type of cross-study is that each participant consumes both types of diets and that their effects can therefore be compared directly on the same person.

As shown in Figure 1, the two diets studied were completely opposite of each other, with 75% of the calories in the low-fat (LF) diet coming from carbohydrates versus only 10% from fat, while in the low-carb (LC) diet, 75% of calories were in the form of fat, compared to only 10% from carbohydrates. The LF diet under study consisted exclusively of foods of plant origin (fruits, vegetables, legumes, root vegetables, soy products, whole grains, etc.), while the LC diet contained mainly (82%) animal foods (meat, poultry, fish, eggs, dairy products).

Figure 1. Comparison of the amounts of carbohydrates, fats and proteins present in the low-carbohydrate (LC) and low-fat (LF) diets consumed by study participants. Adapted from Hall et al. (2021).

The study shows that there is indeed a big difference between the two types of diets in the number of calories consumed by participants (Figure 2). Over a two-week period, participants who ate an LF (low-fat) diet consumed an average of nearly 700 calories (kcal) per day less than an LC (low-carbohydrate) diet. This difference in calorie intake is observed for all meals, both at breakfast (240 calories less for the LF diet), at lunch (143 calories less), at dinner (195 calories less), and during snacks taken between meals (128 calories less). This decrease is not caused by a difference in the appreciation of the two diets by the participants, as parallel analyses did not find any difference in the level of appetite of the participants, nor in the degree of satiety and satisfaction generated by the consumption of either diet. However, the LF diet was composed exclusively of plant-based foods and therefore much richer in non-digestible fibres (60 g per day compared to only 20 g for the LC diet), which greatly reduce the energy density of meals (quantity of calories per g of food) compared to the high-fat LC diet. It is therefore very likely that this difference in energy density contributes to the lower calorie intake observed for the low-fat diet.

Overall, these results indicate that a diet consisting of plants, and thus low in fat and high in complex carbohydrates, is more effective than a diet consisting mainly of animal products, high in fat and low in carbohydrates, to limit calorie intake.

Figure 2. Comparison of the daily calorie intake of participants on a low-carbohydrate (LC) or low-fat (LF) diet. From Hall et al. (2021).

Weight loss
Despite the significant difference in calorie intake observed between the two diets, their respective impact on short-term weight loss is more nuanced. At first glance, the LC diet appeared to be more effective than the LF diet in causing rapid weight loss, with about 1 kg lost on average in the first week and almost 2 kg after two weeks, compared to only 1 kg after two weeks of the LF diet (Figure 3). However, further analysis revealed that the weight loss caused by the LC diet was mainly in the form of lean mass (protein, water, glycogen), while this diet had no significant impact on fat loss during this period. Conversely, the LF diet had no effect on this lean body mass, but did cause a significant decrease in body fat, to around 1 kg after two weeks. In other words, only the LF diet caused a loss of body fat during the study period, which strongly suggests that the decrease in calorie intake made possible by this type of diet may facilitate the maintenance of astable body weight and could even promote weight loss in overweight people.

Figure 3. Comparison of changes in body weight (top), lean mass (middle), and body fat (bottom) caused by low-carbohydrate and low-fat diets. From Hall et al. (2021).

Cardiovascular risk factors
In addition to promoting lower calorie intake and fat loss, the LF diet also appears to be superior to the LC diet in terms of its impact on several cardiovascular risk factors (Table 1):

Cholesterol. It is well established that LDL cholesterol levels increase in response to a high intake of saturated fat (see our article on the issue). It is therefore not surprising that the LF diet, which contains only 2% of all calories as saturated fat, causes a significant decrease in cholesterol, both in terms of total cholesterol and LDL cholesterol. At first glance, the high-fat LC diet (containing 30% of the daily calorie intake as saturated fat) does not appear to have a major effect on LDL cholesterol; however, it should be noted that this diet significantly modifies the distribution of LDL cholesterol particles, in particular with a significant increase in small and dense LDL particles. Several studies have reported that these small, dense LDL particles infiltrate artery walls more easily and also appear to oxidize more easily, two key events in the development and progression of atherosclerosis. In sum, just two weeks of a high-fat LC diet was enough to significantly (and negatively) alter the atherogenic profile of participants, which may raise doubts about the long-term effects of this type of diet on cardiovascular health.

Table 1. Variations in certain risk factors for cardiovascular disease following a diet low in carbohydrates or low in fat. From Hall et al. (2021).

Branched-chain amino acids. Several recent studies have shown a very clear association between blood levels of branched-chain amino acids (leucine, isoleucine and valine) and an increased risk of metabolic syndrome and type 2 diabetes, two very important risk factors for cardiovascular diseases. In this sense, it is very interesting to note that the levels of these amino acids are almost twice as high after two weeks of the LC diet compared to the LF diet, suggesting a positive effect of a diet rich in plants and poor in fats in the prevention of these disorders.

Inflammation. Chronic inflammation is actively involved in the formation and progression of plaques that form on the lining of the arteries and can lead to the development of cardiovascular events such as myocardial infarction and stroke. Clinically, this level of inflammation is often determined by measuring levels of high-sensitivity C-reactive protein (hsCRP), a protein made by the liver and released into the blood in response to inflammatory conditions. As shown in Table 1, the LF diet significantly decreases the levels of this inflammatory marker, another positive effect that argues in favour of a plant-rich diet for the prevention of cardiovascular disease.

In addition to these laboratory data, the researchers noted that participants who were fed the LF diet had a slower heart rate (73 vs. 77 beats/min) as well as lower blood pressure (112/67 vs. 116/69 mm Hg) than observed following the LC diet. In the latter case, this difference could be related, at least in part, to the much higher sodium consumption in the LC diet compared to the LF diet (5938 vs. 3725 mg/day).

All of these results confirm the superiority of a diet mainly composed of plants on all the factors involved in cardiovascular health, whether in terms of lipid profile, chronic inflammation, or adequate control of calorie intake necessary to maintain body weight.

A new metabolite derived from the microbiota linked to cardiovascular disease

A new metabolite derived from the microbiota linked to cardiovascular disease

OVERVIEW

  • Metabolomic screening has identified a new metabolite associated with cardiovascular disease in the blood of people with type 2 diabetes.
  • This metabolite, phenylacetylglutamine (PAGln), is produced by the intestinal microbiota and the liver, from the amino acid phenylalanine from dietary proteins.
  • PAGln binds to adrenergic receptors expressed on the surface of blood platelets, which results in making them hyper-responsive.
  • A beta blocker drug widely used in clinical practice (Carvedilol) blocks the prothrombotic effect of PAGln.

A research group from the Cleveland Clinic in the United States recently identified a new metabolite of the microbiota that is clinically and mechanistically linked to cardiovascular disease (CVD). This discovery was made possible by the use of a metabolomic approach (i.e. the study of metabolites in a given organism or tissue), a powerful and unbiased method that identified, among other things, trimethylamine oxide (TMAO) as a metabolite promoting atherosclerosis and branched-chain amino acids (BCAAs) as markers of obesity.

The new metabolomic screening has identified several compounds associated with one or more of these criteria in the blood of people with type 2 diabetes: 1) association with major adverse cardiovascular events (MACE: myocardial infarction, stroke or death) in the past 3 years; 2) heightened levels of type 2 diabetes; 3) poor correlation with indices of glycemic control. Of these compounds, five were already known: two which are derived from the intestinal microbiota (TMAO and trimethyllysine) and three others that are diacylglycerophospholipids. Among the unknown compounds, the one that was most strongly associated with MACE was identified by mass spectrometry as phenylacetylglutamine (PAGln).

In summary, here is how PAGln is generated (see the left side of Figure 1):

  • The amino acid phenylalanine from dietary proteins (animal and plant origin) is mostly absorbed in the small intestine, but a portion that is not absorbed ends up in the large intestine.
  • In the large intestine, phenylalanine is first transformed into phenylpyruvic acid by the intestinal microbiota, then into phenylacetic acid by certain bacteria, particularly those expressing the porA
  • Phenylacetic acid is absorbed and transported to the liver via the portal vein where it is rapidly metabolized into phenylacetylglutamine or PAGln.

Figure 1. Schematic summary of the involvement of PAGln in the increase in platelet aggregation, athero-thrombosis and major adverse cardiovascular events. From Nemet et al., 2020.

Researchers have shown that PAGln increases the effects associated with platelet activation and the potential for thrombosis in whole blood, on isolated platelets and in animal models of arterial damage.

PAGln binds to cell sites in a saturable manner, suggesting specific binding to membrane receptors. The researchers then demonstrated that PAGln binds to G-protein coupled adrenergic receptors, expressed on the surface of the platelet cell membrane. The stimulation of these receptors by PAGln causes the hyperstimulation of the platelets, which then become hyper-responsive and accelerate the platelet aggregation and the thrombosis process.

Finally, in a mouse thrombus model, it has been shown that a beta blocker drug widely used in clinical practice (Carvedilol) blocks the prothrombotic effect of PAGln. This result is particularly interesting because it suggests that the beneficial effects of beta blockers may be partly caused by reversing the effects of high PAGln levels. The identification of PAGln could lead to the development of new targeted and personalized strategies for the treatment of cardiovascular diseases.