Category: Lipids

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GLAGOV – The Lipid Hypothesis Gains Ground

The results from the recent GLAGOV trial suggest that aggressive lowering of LDL-cholesterol with a PCSK9-inhibitor on top of statin therapy in patients with coronary artery disease may reduce atherosclerotic plaque burden. Although these results provide support for the lipid hypothesis and may have significant implications for the future of cardiovascular medicine, our eyes are still on safety and long-term outcomes.

The lipid hypothesis implies that cholesterol, LDL-cholesterol in particular, is a key factor in causing atherosclerosis and coronary artery disease. In other words, it assumes that measures that elevate blood levels of LDL-cholesterol are bad and actions that lower it are good.

Epidemiological studies have shown that across cultures, cholesterol is linearly related to mortality from coronary artery disease (1).

However, when it comes to overall mortality, the issue is more complicated. Observational studies have shown a correlation between cholesterol levels and overall death rate in young and middle-aged people but not among the elderly (2,3). However, the mortality curve is J-shaped which means that those with the lowest cholesterol levels have increased mortality.

Furthermore, the relationship between cholesterol and mortality may be different for men and women. For example, a Norwegian study (4) found an inverse relationship between cholesterol levels and mortality among women. Hence, according to the authors, moderately raised cholesterol in women may not only be harmless but even beneficial.

The validity of the lipid hypothesis has also been tested in controlled interventional trials.

The Women’s Health Initiative (5) randomly assigned more than 48 thousand women, 50 – 79 years old, to a low-fat intervention or a comparison group. LDL-C was significantly lowered in the intervention group compared to the comparison group. Nonetheless, after six years of follow-up, there were no differences between the groups in the incidence of coronary artery disease and stroke.

The MRFIT trial (6) evaluated 12,866 high-risk middle-aged men who were randomly assigned either to a special intervention program consisting of treatment for high blood pressure, counseling for cigarette smoking, and dietary advice for lowering blood cholesterol levels or to their usual sources of health care in the community. Despite LDL-cholesterol being significantly reduced in the special intervention group compared to the “usual care” group, during a follow-up of seven years, there was no significant difference in total death rates between the groups and no differences in the number of deaths from heart disease.

The results of these two large trials indicate that lifestyle measures aimed at lowering LDL-cholesterol do not improve survival or reduce mortality from heart disease. However, drugs that lower the availability of atherogenic lipoproteins, either by decreasing their production or improving their clearance, might still provide clinical benefit.

Statins 

Since their introduction more than 30 years ago, statin drugs have revolutionized the treatment of coronary heart disease. Randomized double-blind placebo-controlled trials have shown that statins reduce mortality and lower the risk of future cardiovascular events among people with established coronary artery disease.

However, their widespread use among healthy individuals for the purpose of prevention is still debated, and many experts have pointed out that side effects may be more common than previously believed.

Statins are potent inhibitors of cholesterol biosynthesis. Hence, according to the lipid hypothesis, most of the efficacy of statins is due to their cholesterol-lowering effects. However, the overall benefits observed with statins appear to be greater than what might be expected from changes in lipid levels alone, suggesting effects beyond cholesterol lowering.

The Jupiter trial (7) suggested that treatment with statins may have beneficial effects in people with relatively low LDL-cholesterol. The individuals who participated in this trial all had elevated levels of hs-CRP which is a marker of inflammation.

These results may suggest that the efficacy of statins may be explained by other mechanisms than cholesterol lowering, such as reducing inflammation.  The cholesterol-independent or “pleiotropic” effects of statins include improving endothelial function, enhancing the stability of atherosclerotic plaques, decreasing oxidative stress and inflammation, and inhibiting blood clotting mechanisms.

PCSK-9 Inhibitors

The liver is the gatekeeper for low-density lipoprotein (LDL) and is responsible for its production and clearance.

Liver cells express specific receptors on their surface that bind LDL and remove it from the bloodstream. After binding to the LDL-receptor, the LDL/LDL-receptor complex is taken up by endosomes which are special compartments within the cells. The LDL receptor then moves back to the cell surface where it can bind to additional LDL-particles.

This process leads to removal of LDL-particles from the circulation and lower LDL-cholesterol levels. The free LDL left within the cells is transported to lysosomes and degraded into lipids, free fatty acids, and amino acids.

PCSK9 (Proprotein convertase subtilisin-like/kexin type 9) is a protein that regulates the expression of LDL-receptors in the liver.

PCSK9 is produced by liver cells and released into the blood stream. It binds to the LDL-receptor on the surface of liver cells, together with LDL. It also moves into the cell, together with the LDL-receptor/LDL complex.

After LDL is released from this complex, the LDL-receptor/PCSK9 complex is taken up by lysosomes for degradation, preventing the recycling of the LDL-receptor to the cell surface. Thus, PCSK9 is responsible for the degradation of LDL-receptors and therefore plays a critical role in the regulation of LDL-cholesterol levels.

Genetic mutations that lead to a loss of PCSK9 function are found in 1–3 percent of the population. These mutations are associated with very low LDL cholesterol levels and a lower incidence of CAD.

PCSK9-inhibitors are monoclonal antibodies directed against PCSK9. They lower LDL cholesterol by blocking the interaction of PCSK9 with the LDL-receptor on the surface of liver cells. This allows LDL-receptors to recycle to the cell surface, after releasing LDL within the cell, instead of being taken up and degraded in lysosomes. Increased concentration of LDL receptors on the surface of liver cells improves clearance of LDL, which will be reflected as lower levels of LDL-cholesterol.

Large-scale randomized clinical trials have shown that adding PCSK9 inhibitors on top of statin therapy in patients with established cardiovascular disease may provide some clinical benefit (8).

Can PCSK9-Inhibitors Reduce the Burden of Atherosclerosis?

Atherosclerosis is a key underlying component of cardiovascular disease. It is characterized by a chronic inflammation of the arterial wall, resulting from complex interactions between lipoproteins, white blood cells, the immune system, and several other factors.

Atherosclerotic lesions or plaques may cause arterial narrowing which may ultimately limit blood flow. Rupture of an atherosclerotic plaque may lead to thrombosis causing a sudden occlusion of the artery.

In theory, adding a PCSK9-inhibitor on top of statin therapy in patients with cardiovascular disease might reduce atherosclerotic plaques, reduce the risk of cardiovascular events such as heart attacks and strokes, and mortality may be reduced.

Studies have demonstrated good tolerability and efficacy of these drugs, with reductions in LDL-cholesterol ranging from 39-62 percent, compared with placebo, on top of maximally tolerated statin therapy and diet (9,10).

The big question is whether such a massive lowering of LDL cholesterol will provide clinical benefit and more importantly; will it cause harm? Unfortunately, these issues will not be answered until next year when the results from the large clinical trials become available (11).

However, recent evidence suggests that that the  PCSK9-inhibitor evolocumab may indeed reduce atherosclerotic plaque volume. This is based on Amgen’s recent press release stating that the so-called GLAGOV study showed positive results (12).

GLAGOV

The GLAGOV study is a Phase 3, multicenter, double-blind, randomized, placebo-controlled trial designed to test whether treatment with the evolocumab in patients with established coronary artery disease modifies atherosclerotic plaque build-up in the coronary arteries of patients already treated with statins.

A total of 968 patients undergoing coronary angiography were randomized to receive either monthly subcutaneous injections of evolocumab 420 mg or corresponding placebo.

Intravascular ultrasound (IVUS) was used to quantify plaque volume in the coronary arteries. This is a high-resolution imaging tool that allows for the quantification of atherosclerotic plaques.

According to the press release, no new safety concerns were identified in the GLAGOV trial. The incidence of treatment-emergent adverse events was comparable among both groups. The primary endpoint was the change in percent atheroma volume from baseline to week 78 compared with placebo.

Currently, no further details are available on the results of the trial. These will be presented at the upcoming American Heart Association (AHA) Scientific Sessions in November 2016.

The GLAGOV results are concordant with the lipid hypothesis, suggesting that aggressive lowering of LDL-cholesterol will halt the atherosclerotic process. However, it has to be kept in mind that PCSK9-inhibitors affect several other lipid parameters. For example, treatment with evolocumab significantly reduces blood levels of lipoprotein (a) which may have significant clinical implications (13).

GLAGOV is the first randomized placebo-controlled trial showing a positive effect on atherosclerotic plaque volume by adding a PCSK9-inhibitor on top of statin therapy in patients with coronary artery disease. Whether this transforms into clinical benefit remains to be seen. Despite these promising results our eyes must still be on long-term efficacy and safety concerns.

So, until more data is available, GLAGOV may reflect new hopes for the future but could also turn out to be nothing more than empty promises.



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Apolipoprotein E – ApoE Explained

Estimated reading time: 8 minutes

Apolipoprotein E (ApoE) is one of the proteins the body uses to transport fats (lipids) in the bloodstream from one tissue or cell type to another. It is essential for healthy metabolism of cholesterol and triglycerides, two important types of fats the body has to deal with regularly.

The relationship between ApoE and heart disease has been studied quite intensively in recent years. Furthermore, the association between a subtype of ApoE called ApoE4 has received much attention because of its correlation with increased risk of Alzheimer’s disease.

Lipoproteins are a combination of proteins (apolipoproteins) and fats such as cholesterol, phospholipids, and triglycerides. The primary role of the apolipoproteins is to bind lipids to form a water soluble compund, enabling transport of different types of lipids through the circulatory systems.

There are several types of apolipoproteins. Despite their important role in lipid metabolism, the apolipoproteins also seem to be involved in several disease processes. For example, apolipoprotein B (apoB) is known for its association with atherosclerosis and coronary artery disease.

ApoB is present in lipoprotein particles such as low-density lipoprotein (LDL), very-low density lipoprotein (VLDL) and lipoprotein(a). These lipoproteins are often termed atherogenic because they appear to play a role in atherosclerosis and heart disease. Several studies have shown that high levels of apoB are associated with increased risk of cardiovascular disease (1).

ApoE is typically found in chylomicrons, VLDL, and intermediate density lipoproteins (IDL).  In humans, ApoE is polymorphic, meaning that there are several subtypes of the protein with several different functions.

What is ApoE and What Does It Do?

ApoE is a chain of 299 amino acids. It is primarily produced by the liver and white blood cells called macrophages. In the central nervous system, ApoE is mainly generated by a type of nerve cells called astrocytes. ApoE is the principal carrier of cholesterol within the brain.

Human ApoE exists as three common isoforms, ApoE2, ApoE3, and ApoE4. The differences between the three isoforms are limited to two amino acids at spots 112 and 158 in the amino acid chain where either cysteine or arginine is present. These amino acid differences are important for the protein’s ability to bind to lipids and cell receptors.

Lipoprotein particles containing ApoE carry both cholesterol and triglycerides. ApoE appears to play a vital role in regulating the blood levels of these fats. Its primary purpose is to promote clearance of triglyceride-rich lipoproteins from the circulation.

ApoE3 is often regarded as the parent form and is associated with normal plasma cholesterol levels. The ApoE2 and ApoE4 isoforms, on the other hand, are related to lipid abnormalities mainly caused by abnormal metabolism of triglyceride-rich lipoproteins, primarily VLDL.

ApoE Metabolism – The Different Roles of ApoE3, ApoE2, and ApoE4

Following a fatty meal, triglycerides are transported in the lymphatic system and blood by lipoproteins called chylomicrons. After being broken down (lipolysis) in the circulation, chylomicrons derived from the intestine and VLDL derived from liver cells become so-called remnant lipoprotein particles. The ApoE part of the remnant particles binds to LDL receptors, primarily in the liver, hence initiating the removal of the particles from the circulation (2). This process is an essential part of healthy lipid metabolism and a key factor in maintaining normal blood levels of cholesterol and triglycerides.

Some VLDL remnants are cleared rapidly whereas others undergo further lipolysis and are converted to IDL and finally to LDL. However, the LDL particles do not contain ApoE. The primary lipoprotein in LDL is ApoB, and the clearance of LDL from the circulation is mediated by the binding of ApoB to the LDL receptor.

The ApoE2 isoform differs from ApoE3 by a single amino acid substitution located near the LDL receptor recognition site. It exhibits impaired binding to the receptor and an inability to promote clearance of triglyceride-rich lipoprotein remnant particles. Hence, ApoE2 is associated with raised levels of both cholesterol and triglycerides.

Type-III hyperlipoproteinemia is a rare genetic disorder characterized by high blood levels of VLDL, triglycerides, and cholesterol (3). Most cases result from inheritance of two genes that code for ApoE2.

ApoE4, on the other hand, seems to accelerate the clearance of VLDL and remnant lipoproteins. However, LDL levels are increased, possibly because of down-regulation of LDL receptors or due to a competition between remnant lipoproteins and LDL for a place on the receptors (4).

There are three different types of the ApoE gene, called alleles; E2, E3, and E4. We all carry two copies of the APOE gene. The combination of alleles determines our ApoE3 genotype. There are six possible combinations (genotypes) for ApoE; E2/E2, E3/E3, E4/E4, E2/E3, E2/E4, E3/E4.

The Genetic Aspects of ApoE

The ApoE gene provides instructions for making the ApoE protein. There are three different types of the ApoE gene, called alleles; E2, E3, and E4.

We all carry two copies of the APOE gene. The combination of alleles determines our ApoE3 genotype.

There are six possible combinations (genotypes) for ApoE

  • E2/E2
  • E3/E3
  • E4/E4
  • E2/E3
  • E2/E4
  • E3/E4

The ApoE2 allele is the rarest, and the ApoE3 allele is the most common. ApoE3 is present in more than half of the population. Carrying at least one ApoE2 allele appears to reduce the risk of developing Alzheimer’s disease whereas the Apoe4 allele is associated with increased risk of developing the disease.

The ApoE2 allele is found in approximately 7 percent of the population (5). Individuals with the E2/E2 combination may clear dietary fat slowly and are at greater risk of heart disease.

The ApoE4 allele is present in approximately 14% of individuals. Its presence is associated with increased risk of atherosclerosis (6), Alzheimer’s disease (7) and impaired cognitive function (8).

ApoE4 and Alzheimer’s Disease

Alzheimer’s disease is the most common form of dementia. The lifetime risk of developing the disease is approximately 20 percent for women and 10 percent for men.

The science of Alzheimer’s disease has come a long way since 1906 when a German neurologist and psychiatrist named Dr. Alois Alzheimer first described the key features of the disease. He noticed abnormal deposits in the brain of a 51-year old woman who had dementia. Researchers now know that Alzheimer’s disease is characterized by brain abnormalities called plaques and tangles.

The exact cause of Alzheimer’s disease is unknown, but some risk factors have been described. The risk of developing the disease increases with age. Family history also plays a role; there’s a higher risk of Alzheimer’s if a family member has the disease.

The early-onset form of Alzheimer disease which typically develops before age 65 accounts for less than one percent of cases. It follows an autosomal dominant inheritance pattern associated with gene mutations that alter so-called amyloid-beta protein production, aggregation, or clearance in the brain.

The genetic basis of late-onset Alzheimer disease is more complex. Among the genetic factors that often appear to be involved is the presence of the ApoE4 allele. ApoE is critical for lipid transport in the brain and contributes to the maintenance and repair of nerve cells.

ApoE4 is a major genetic risk factor for late-onset Alzheimer’s disease (9). Individuals carrying the E4 allele are at increased risk of Alzheimer’s disease compared with those carrying the more common E3 allele, whereas the presence of the E2 allele decreases risk (10).

Having one allele of ApoE4 increases the risk of Alzheimer’s disease, and if two ApoE4 alleles are present, the risk is even higher.

However, it is important to acknowledge that the association between ApoE4 and Alzheimer’s disease is complex. Many individuals with the ApoE4 allele never develop the disease and many patients with Alzheimer’s disease do not have the ApoE4 allele.

The risk of developing Alzheimer’s disease also appears to be affected by environmental factors. Diabetes, high blood pressure, obesity, depression, physical inactivity, smoking, and cognitive inactivity or low educational attainment all seem to increase the risk of the disease (11).

So although there’s no definitive way to prevent the Alzheimer’s disease, not smoking, keeping blood pressure at healthy levels, regular exercise, maintaining a healthy weight and eating a healthy diet are all sensible approaches to reduce the risk of the disease.

Is It Possible To Measure ApoE Status?

Measurements of the concentration of apolipoprotein B and apolipoprotein A1 in blood or plasma are often done to assess cardiovascular risk. However, measurements of ApoE and its isoforms have limited value in clinical practice and are therefore seldom performed.

Genetic testing is available to define the ApoE genotype. The E4/E4 genotype has the strongest association with the risk of Alzheimer’s disease. The presence of the E2 allele seems to be associated with less risk of Alzheimer’s disease. However, in some cases, this allele is associated with lipid abnormalities and increased risk of heart disease.

The Take-Home Message

Apolipoprotein E (ApoE) plays a major role in the metabolism of dietary fat. It is an important regulator of blood levels of both cholesterol and triglycerides. and plays an integral part in the transport of these fats in the body.

There are three different types of the ApoE gene, called alleles; E2, E3, and E4. These genes provide code for the production of the three different isoforms of ApoE called ApoE2, ApoE3, and ApoE4.

ApoeE3 is often regarded as the parent form. The presence of ApoE2 is associated with increased risk of lipid orders and heart disease. The presence of ApoE4 is associated with increased risk of late-onset Alzheimer’s disease.

Measurements of blood levels of ApoE and its isoforms are seldom used in clinical practice. Genetic testing is available to define the ApoE genotype.




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High Carbohydrate Intake Worse than High Fat for Blood Lipids

Estimated reading time: 5 minutes

Data presented at the World Heart Federation’s World Congress of Cardiology & Cardiovascular Health 2016 (WCC 2016) in Mexico City may radically change our perspective on how carbohydrates and different types of fats affect blood cholesterol and other lipid biomarkers. The presentation was based on data from the Prospective Urban Rural Epidemiological (PURE) study. The data have not been published yet, and the results are only available in an abstract (1).

The study, presented by researchers from McMaster University, Hamilton, Canada, addresses how carbohydrate and fat intake affected blood lipid profiles in 145.000 individuals living in nineteen low- to high-income countries. The researchers conclude that the message to reduce the intake of saturated fats for the purpose of lowering cholesterol and thus decrease risk of cardiovascular disease may be misleading

For decades, blood cholesterol was assumed to be a robust surrogate marker to predict the risk of heart disease. A reduction in saturated fats is recommended to reduce cholesterol levels, and carbohydrates are placed at the bottom of the food pyramid, mainly because they tend to lower cholesterol levels. Public health authorities have recommended that 60 percent of daily calories should come from carbohydrates.

However, the low-fat, high-carbohydrate approach has recently been challenged, and the authors of the recent study point out that there are no data from low and middle-income countries where more than 80 percent of cardiovascular disease occurs.

The PURE Data on Nutrition and Lipids

The goals of the study were to describe the association between nutrient intake and blood lipids and to examine the effect of iso-caloric replacement of nutrients on blood lipids.

The habitual food intake of 145,275 participants in 19 high, middle and low-income countries who were enrolled in the PURE study was prospectively measured using validated food frequency questionnaires.

The lipid biomarkers addressed in the study:

  • Total cholesterol (TC)
  • LDL cholesterol (LDL-C)
  • HDL cholesterol (HDL-C)
  • Triglycerides (TG)
  • Apolipoprotein A (ApoA)
  • Apolipoprotein B (ApoB)

The macronutrients addressed in the study:

  • Carbohydrates
  • Saturated fatty acids (SFA)
  • Monounsaturated fatty acids (MUFA)
  • Polyunsaturated fatty acids (PUFA)

Higher carbohydrate intake was associated with lower TC and LDL-C but also with lower HDL-C and ApoA levels, leading to higher TC/HDL-C and ApoB/ApoA ratios and higher TGs. The apoB/apoA ratio has repeatedly been shown to be a better marker of risk than lipids, lipoproteins and lipid ratios (2)

A higher intake of SFAs was associated with higher LDL-C and lower TG levels. Higher MUFA intake was associated with lower TC, LDL-C, and higher ApoA. Higher PUFA intake was associated with lower TC and LDL-C and paradoxically higher ApoB level.

Iso-caloric replacements of carbohydrates with SFAs increased TC by 3%, LDL-C by 5% and HDL-C by 1% and decreased TG by 5%. Replacement of carbohydrates with MUFA led to a 2% decrease in LDL-C, 3% decrease in TC/HDL-C ratio, and 1% decrease in ApoB/ApoA ratio. Replacing carbohydrates with PUFAs was associated with little change in lipid markers.

The authors concluded that higher carbohydrate intake has the most adverse impact on lipid profiles and replacing it with saturated fat improved HDL-C and TG and replacing it with MUFAs improved TC/HDL-C and ApoB/ApoA.

“These data from a large global study indicate that guidelines on dietary fats and carbohydrates require re-evaluation.”

Placing carbohydrates at the bottom of the food pyramid based on their effect on blood cholesterol may have been a mistake. In fact, data show that replacing dietary carbohydrates with different types of fat may improve lipid profile.

The Bottom Line

Public health authorities, including the American Heart Association (AHA) and the World Health Organization (WHO) recommend that 60% of calories should come from carbohydrates and only 5% to 6% of calories from saturated fat.

In the above study, the only benefit of a high carbohydrate diet was a lowering of TC and LDL-C. However, the effect on other lipid biomarkers such as HDL-C, TG, and ApoB/ApoA ratio may be harmful.

A diet rich in SFAs raised TC and LDL-C but lowered TG while a diet rich in MUFAs improved all lipid biomarkers. A diet high in PUFAs had a mixed effect on lipid biomarkers.

The study suggests that placing carbohydrates at the bottom of the food pyramid based on their effect on blood cholesterol was a mistake. In fact, the data show that replacing dietary carbohydrates with different types of fat may improve lipid profile.

In an interview on Medscape, Dr. Mahshid Dehghan, the principal author of the abstract said (3):

To summarize our findings, the most adverse effect on blood lipids is from carbohydrates; the most benefit is from consumption of monounsaturated fatty acids; and the effect of saturated and polyunsaturated fatty acids are mixed. I believe this is a big message that we can give because we are confusing people with a low-fat diet and all the complications of total fat consumption, and WHO and AHA all suggest 55% to 60% of energy from carbohydrates.

Today, most experts agree that diets high in SFAs or refined carbohydrates are not be recommended for the prevention of heart disease. However, it appears that carbohydrates are likely to cause a greater metabolic damage than SFAs in the rapidly growing population of people with metabolic abnormalities associated with obesity and insulin resistance.

I assume we all agree that partially hydrogenated fats (trans-fats) should be avoided. However, the singular focus on reducing the intake of SFAs, and dietary fats in general, may have been counterproductive and promoted the rapidly growing popularity of refined carbohydrates. The nutritional data from the PURE study clearly suggest that it is time to shift our focus away from reducing fat in our diet towards reduced consumption of carbohydrates.




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Fructose Restriction – An Effective Lipid Intervention?

The association between lipid disorders and heart disease is well known. Medical checkups usually involve measurements of cholesterol and other lipid parameters, and most doctors advise their patients on how to improve their lipid pattern.

Dietary interventions to lower the risk of heart disease commonly aim at reducing blood levels of cholesterol, LDL cholesterol in particular. This is one of the main reasons why low-fat diets are usually recommended by public health authorities. Reducing the amount of saturated fat and cholesterol, in particular, is believed to be effective. However, in an era where metabolic abnormalities associated with obesity and insulin resistance are becoming increasingly common, other measures might be more effective.

Lately, low-carbohydrate diets have become popular for patients with obesity and metabolic syndrome. Metabolic syndrome is characterized by a large waistline, high blood pressure, glucose intolerance, low HDL cholesterol, and elevated triglycerides. It has been proposed that carbohydrate restriction may improve this lipid pattern as it raises HDL cholesterol and lowers triglycerides. However, some experts have concluded that carbohydrate restriction may be harmful because of the possible detrimental effects of increased LDL cholesterol (1).

Recently, it has become more common to assess the amount of circulating lipoprotein particles, rather than the amount of cholesterol itself. Such tests may be more accurate, particularly in people with metabolic syndrome. How these biomarkers are affected by dietary modification is an exciting and growing area of research. For the time being, we can call these lipid biomarkers nontraditional because their use is not widespread in the clinical setting.

Nontraditional Lipid Biomarkers

Scientific data suggest that the number of LDL particles is a stronger risk factor than LDL cholesterol (2). Furthermore, LDL particle size may be important as small particles are more strongly associated with the risk of heart disease than larger particles.

The triglyceride/HDL-cholesterol ratio appears to be a useful marker of the risk of coronary artery disease (3). A high ratio correlates with small LDL particle size and insulin resistance.

Apolipoprotein B (apoB) is a major component of atherogenic lipoprotein particles such as LDL, VLDL and Lp(a). Each of these particles contains a single apoB molecule. Hence, apoB measurements reflect the number of atherogenic particles, most of which are LDL particles.

Several studies suggest that apoB is a better predictor of heart disease risk than LDL cholesterol (4). Furthermore, it has been shown that apoB may be elevated despite normal or low concentrations of LDL cholesterol (5).

Apolipoprotein C-III (apo C-III) is found on the surface of triglyceride-rich lipoproteins (6). High levels of apo-C-III are associated with high triglyceride levels and increased risk of cardiovascular disease. Apo-C-III may contribute to the development of atherosclerosis by several mechanisms (7).

Apolipoprotein E (APOE) is a lipoprotein found primarily in chylomicrons and intermediate-density lipoprotein (IDL). APOE transports lipoproteins, fat-soluble vitamins, and cholesterol. The ApoE4 isoform is associated with lipid disorders, high blood cholesterol, and increased risk of coronary heart disease and stroke (8).

There are at least three slightly different alleles of the gene that codes for APOE. The major alleles are called e2, e3, and e4. The most common allele is e3, which is found in more than half of the general population. The e4 allele of APOE is associated with increased risk of cognitive decline and Alzheimer’s disease.

Lipid Biomarkers in the Metabolic Syndrome – The Role of Fructose

The metabolic syndrome is associated with increased risk of cardiovascular disease (9). It has been proposed that reducing the intake of added sugar may correct some of the metabolic abnormalities associated with this syndrome. The issue was recently addressed in a paper published by Robert Lustig and coworkers from the University of California (10).

Lustig studied 43 obese children (ages 8-19) with metabolic abnormalities typical of the metabolic syndrome. All were high consumers of added sugar in their diets (e.g. soft drinks, juices, pastries, breakfast cereals, salad dressings, etc.).

The children were fed the same calories and percent of each macronutrient as their home diet; but within the carbohydrate fraction, the added sugar was removed, and replaced with starch. For example, pastries were taken out, and bagels put in; yogurt was taken out, baked potato chips were put in; chicken teriyaki was taken out, turkey hot dogs were put in. Whole fruit was allowed.

After ten days, diastolic blood pressure fell, insulin resistance decreased, liver tests improved, and triglycerides, LDL cholesterol, and HDL cholesterol all improved.

Recently, more results from this study were published by Gugliucci and coworkers in the journal Atherosclerosis (11). The paper presents data on the effect of fructose restriction on the lipoprotein profile of these same children.

A total of 37 children participated in this part of the trial. They were given food and drinks totaling the same number of calories, fat, protein, and carbohydrates as their typical diets. The only change was their sugar intake. Dietary sugar decreased from 28 percent to 10 percent, and fructose from 12 percent to 4 percent of total calories.

After nine days, the researchers found a 33 percent drop in triglycerides, a 49 percent reduction in apoC-III  and dramatic reductions in small, dense LDL particles. LDL size was significantly increased. Significant reductions were also found in apoB and apoE. The TG/HDL-C ratio decreased from 3.1 to 2.4. These changes in fasting lipid profiles correlated with changes in insulin sensitivity.

The Bottom Line

The above data suggest that the lipid abnormalities found in children with obesity and metabolic syndrome can be dramatically improved short-term by reducing the intake of added sugar, particularly fructose. This may implicate fructose consumption as a possible underlying cause of lipid abnormalities associated with the metabolic syndrome.

Interestingly, all of the lipid parameters tested were improved by fructose restriction. The effect on apoB and apo-CIII suggests that the availability of atherogenic LDL and triglyceride-rich lipoproteins was significantly reduced.

The main weakness of Lustig’s and Gugliucci’s studies is that there was no control group. It was not a controlled randomized trial. However, this does not mean that the results shouldn’t be taken seriously. But we will surely need a randomized study to confirm the findings

Recently, a meta-analysis of randomized controlled trials on the effects of low-carbohydrate diets v. low-fat diets on body weight and cardiovascular risk factors was published in the British Journal of Nutrition (1). This meta-analysis demonstrated that compared with participants on low-fat diets, participants on low carbohydrate diets experienced a greater reduction in body weight and blood triglycerides and a greater increase in HDL cholesterol and LDL cholesterol. Despite the positive metabolic effects, the authors concluded that the beneficial changes of the low-carbohydrate diets must be weighed against the possible detrimental effects of increased LDL cholesterol.

Following this publication, I had the pleasure of co-authoring a letter to the editor of the journal which was published a few weeks later (12). In the letter we point out that although the exact mechanisms of low-carbohydrate diets are still debated (improved insulin dynamics, spontaneous reduction in energy intake, increased protein intake, etc), and they are by no means a panacea, the most robust effects of any single long-term dietary intervention in terms of improvements in parameters of insulin resistance, glucose metabolism, lipid biomarkers and cardiovascular disease risk, is the restriction of carbohydrate intake. Despite the author’s conclusions to the contrary, we believe that their meta-analysis supports this premise.

The recently published data by Gugliucci and coworkers clearly suggest that fructose restriction may be one of the magic bullets we need to correct the lipid abnormalities associated with obesity and the metabolic syndrome. If confirmed by randomized studies, this simple intervention may improve the health of millions of people worldwide.




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Do Lipid Biomarkers Like Cholesterol Predict Cancer Risk?

Lipid biomarkers are frequently used to assess the risk of heart disease.  A simple blood test provides information about LDL-cholesterol (LDL-C) (1), commonly nicknamed the bad cholesterol and HDL-cholesterol (HDL-C) (2), often called the good cholesterol. Triglycerides are usually measured as well (3).

For many different reasons, lowering LDL-C has become a primary target for the prevention of heart disease. Evidence suggests a relationship between LDL-C and the risk of coronary heart disease. Lifestyle measures that lower LDL-C are usually recommended, and statins (cholesterol-lowering drugs) are used by millions of people worldwide to lower LDL-C.

Blood levels of triglycerides are also associated with the risk of heart disease (4). Furthermore, there is an inverse correlation between HDL-C and cardiovascular risk. Hence, high HDL-C levels are associated with less risk of heart disease, and low levels are related to increased risk.

But, what about the relationship between lipid biomarkers and cancer? Do we find the same pattern there?

Cancer is the second leading cause of death in most western countries. Diet, smoking, and obesity are known risk factors for cancer. These risk factors often correlate with alterations in blood lipid markers.

Lipid Biomarkers

Because fats are insoluble in water, cholesterol and triglycerides cannot be transported in blood on its own. Instead, cholesterol is attached to hydrophilic proteins that function as transport vehicles carrying different types of fats such as cholesterol and triglycerides. These combinations of fats and protein are termed lipoproteins. The lipoprotein particles vary in the primary lipoprotein present and the relative contents of the different lipid components.

The lipoproteins are classified according to their chemical properties. There are five major types; chylomicrons, very low-density lipoprotein (VLDL), intermediate-density lipoprotein (IDL), low-density lipoprotein (LDL) and high-density lipoprotein (HDL).

Measuring the amount of cholesterol carried by the different types of lipoproteins has become standard practice. Thus, LDL-C reflects the amount of cholesterol carried by LDL and HDL-C reflects the amount off cholesterol carried by HDL.

However, measuring the concentration of the lipoproteins themselves may be more informative than measuring the amount of cholesterol within these particles. There is substantial evidence that some lipoproteins play a fundamental role in heart disease and their interaction with the arterial wall appears to initiate the cascade of events that leads to atherosclerosis. Lipoproteins that promote atherosclerosis and cardiovascular disease are termed atherogenic. Apolipoprotein B (apo B) is a major component of atherogenic lipoproteins (5).

Apo B occurs in 2 main forms, apo B-48, and apo B-100. Apo B-48 is mainly synthesized by the small intestine and is primarily found in chylomicrons. Apo B-100 is the protein found in lipoproteins synthesized by the liver. From the viewpoint of cardiovascular risk, apo B-100 is the important one.

Apo B-100 is the primary lipoprotein in LDL (6) and other lipoproteins that promote atherosclerosis, such as VLDL and lipoprotein(a) (7).

Apolipoprotein A-I (Apo A-I) is the main protein component of HDL. As with HDL-C, low levels of Apo A-I are associated with increased risk of heart disease and high levels seem to be protective.

Apo B, apo A-I and the apo B/apo A-I ratio have been reported as better predictors of cardiovascular events than LDL-C (8).

Lipid Biomarkers and Cancer Risk

The role of lipid biomarkers in assessing the risk of cancer has not been studied in detail. However, lipid metabolism has now been accepted as a major metabolic pathway involved in many aspects of cancer cell biology (9). In this context, the contribution of dietary factors, such as different types of fatty acids, carbohydrates, and added sugars may be of importance. Hence, it is likely that future therapeutic strategies for cancer will include dietary regimes. Blood lipids and lipoproteins may influence the risk of cancer through insulin resistance, inflammation, and oxidative stress (10).

Some studies have found an inverse association between total cholesterol and the risk of cancer, suggesting that low blood cholesterol may increase cancer risk (11,12, 13). This has led some experts to conclude that too much lowering of cholesterol may be harmful.

However, other studies have found a positive correlation between total cholesterol and the risk of cancer (14).

Very few studies have addressed the association between novel biomarkers such as Apo B-100 and apo A-I and cancer risk.

So it appears that the relationship between lipid biomarkers and cancer risk has not been clarified yet. However, a recently published paper addressing lipid biomarkers and long-term risk of cancer in women may have cast some light on the issue.

Lipids Biomarkers and Cancer Risk in the Women’s Health Study

Chandler and coworkers evaluated the association between plasma lipids and risk of cancer, in a prospective analysis in a large cohort of women aged ≥45, who were free of cancer and heart disease at baseline. The results were recently published on-line in the American Journal of Clinical Nutrition (15).

Breast cancer, colorectal cancer, and lung cancer are the most frequently diagnosed cancers in women. The association between lipid biomarkers and the risk of these cancers was addressed in the study.

 

Although apo A-I is correlated with HDL-C, and apo B-100 is correlated with total cholesterol and LDL-C, the authors hypothesized that apo A-I and apo B-100 might provide a superior risk prediction for certain cancers than would standard lipid markers.

A total of 15.602 females were followed for a median of 19 years. There were 2.163 incident cancer cases (864 breast cancers, 198 colorectal cancers, and 190 lung cancers).

After multivariable adjustment, women in increasing quartiles of Apo A-I and HDL-C had significantly decreased risk of incident total cancer. The association was slightly attenuated after adjustment for body mass index. Total cholesterol, LDL -C, triglycerides and Apo B-100 were not significantly associated with total cancer incidence.

Women in increasing quartiles of apo B-100 and triglycerides had increased risk of colorectal cancer. HDL-C showed an inverse correlation with the risk of colorectal cancer.

No lipid biomarkers were significantly associated with increased risk of breast cancer.

Women in increasing quartiles of HDL-C and Apo-A1 had significantly decreased risk of lung cancer. After adjustment for BMI, the correlation was only significant for HDL-C.

LDL-C was not significantly associated with risk of total cancer or any site-specific cancers.

The authors of the paper concluded that lifestyle interventions that reduce apo-B 100 or raise HDL-C may be associated with ireduced cancer risk.

The Bottom-Line

Recent evidence suggests that when it comes to cancer, a high-risk lipid profile is somewhat different from that used to predict the risk of heart disease.

Today, LDL-C is a primary target for cardiovascular prevention. However, this biomarker appears pretty useless when it comes to predicting the risk of cancer.

Low HDL-C, on the other hand, seems to be a strong predictor of cancer risk and so are low levels of Apo A-I, the main protein in HDL.

The findings of the recent study by Chandler and coworkers support a possible role of lipid metabolism in the development of cancer. The authors of the paper conclude that the attenuation of the associations between lipids and cancer risk, when adjusted for body mass index, suggests that blood lipids may be involved in the development of cancer through pathophysiologic processes related to obesity.

Low HDL-C and Apo A-I levels are few of the key features of the metabolic syndrome which is also characterized by elevated triglycerides, central obesity, hypertension, and glucose intolerance.

A recent study in the prospective Metabolic Syndrome and Cancer Project suggested a potential role of triglycerides in the development of cancer (16).

Several observational studies suggest that central obesity (17), insulin resistance (18), hyperinsulinemia and low adiponectin (19) levels are associated with increased risk of cancer. Although the mechanisms of this link remain obscure, it is possible that hyperinsulinemia in itself is important in linking insulin resistance to cancer (20). Insulin is a known growth factor and has been put forth as a causative factor in cardiovascular disease. Also, hyperinsulinemia promotes inflammation, which is an established risk factor for the development of cancer (21).

The association between lipid biomarkers and cancer may imply that dietary measures aimed at raising HDL-C and Apo-I, and lowering triglycerides and Apo B-100 may reduce the risk of cancer. However, due to the observational nature of the study, this can only be regarded as a hypothesis.

Although low-fat diets may help to reduce LDL-C, low-carbohydrate diets are more effective in raising HDL-C and reducing inflammation (22, 23). Other lifestyle interventions for cancer prevention such as regular exercise and smoking cessation are also useful in raising HDL-C.



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