Hyperlipidemia

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Chapter 18 Hyperlipidemia

With contribution from Professor Manohar Garg

Introduction

Hyperlipidemia is a heterogeneous disorder characterised by increased circulating levels of plasma cholesterol, low-density lipoprotein (LDL)-cholesterol, triglycerides and apolipoprotein-B (apoB) as well as reduced high-density lipoprotein (HDL)-cholesterol concentration.1 The primary lipid abnormality involved in the development of hyperlipidemia is an increase in circulating free (non-esterified) fatty acids originating from adipose tissue, caused by a down-regulation of signalling pathways, as well as inadequate esterification and metabolism.2 Reduced retention of fatty acids by adipose tissue results in an increased flux of non-esterified or free fatty acids (FFA) returning to the liver, stimulating hepatic triglyceride synthesis, promoting production of apoB and assembly/secretion of very low-density lipoprotein (VLDL).3 Presence of increased plasma triglyceride concentration results in the increased production of triglyceride rich HDL particles that are more likely to be catabolized resulting in reduced HDL-cholesterol. Elevated VLDL particles are lipolyses, converted into small dense (highly atherogenic) LDL particles with reduced receptor-mediated clearance, prolonged retention in circulation and an increased susceptibility to peroxidation.4 A strong independent association between elevated levels of LDL-cholesterol and increased incidence of coronary heart disease (CHD) has been established.5, 6

Prevalence and economy of burden

The World Health Organization (WHO) estimated that hyperlipidemia is associated with more than 50% of global cases of ischemic heart disease and >4 million deaths/year.7 Most (80%) lipid disorders are related to diet and lifestyle, although familial disorders (20%) are important as well. The basic categories of hyperlipidemia include: increased LDL-cholesterol, reduced HDL-cholesterol, excess lipoprotein(a) (LPa), hypertriglyceridemia, atherogenic dyslipidemia, and mixed lipid disorders.8 Most patients with CHD have mixed hyperlipidemia (e.g. elevated LDL-cholesterol and low HDL-cholesterol), which is also commonly seen in patients with diabetes mellitus.

The American Heart Association estimates that more than 98 million Americans have total cholesterol levels >5.18mmol/L (200mg/dL), which is considered a moderately high level, and more than 34 million adult Americans have levels >6.2mmol/L (240mg/dL), which is considered a high level necessitating treatment.9 A recent Australian study set out to estimate the prevalence of selected diagnosed chronic diseases among patients (n = 9156) attending general practice reported prevalence of hyperlipidemia to be 15.9%.10 Prevalence of dyslipidemia in a professional population in Beijing, China has been reported to be 52.7% for males and 42.9% for females with at least 1 abnormality in the blood lipid profile.11

Increasing evidence supports triglyceride (TG) concentration as a risk factor for cardiovascular disease,12 however, the exact role of hypertriglyceridemia in the development of CVD is not known. A recent study examined the prevalence of hyperlipidemia in 5610 adults aged 20 years or older enrolled in the National Health and Nutrition Examination Surveys (NHANES) from 1999 to 2004.13 Unadjusted prevalence rates (percentages) of TG concentration of 1.695mmol/L (150mg/dL) or higher occurred in 33.1% of participants, a concentration of 2.26mmol/L (200mg/dL) or higher occurred in 17.9% of participants, a concentration of 5.65mmol/L (500mg/dL) or higher occurred in 1.7% of participants, and a concentration of 11.3mmol/L (1000mg/dL) or higher occurred in 0.4% of participants.

The total cost associated with cardiovascular diseases and stroke in the United States, many of which are related to dyslipidemia, was estimated to exceed $400 billion in 2006.14 Total costs include medical services (direct costs) as well as lost wages (indirect costs). While the health care system is only associated with the direct costs, these are nearly two-thirds of total costs. Costs of cardiovascular disease and stroke vary widely around the world, but in every instance, costs are substantial.15 Closely related to dyslipidemia is diabetes mellitus. Persons with diabetes mellitus have average LDL-cholesterol levels in excess of 140mg/dL, and most require drug therapy.16

In light of the increasing prevalence and health consequences associated with CHD, there is an emerging need to identify lifestyle factors and treatments which alleviate risk factors associated with its development and progression. Hyperlipidemia contributes to the underlying mechanisms of atherosclerotic disease, promoting endothelial dysfunction, oxidative stress and pro-inflammatory pathways.

The National Heart Foundation (NHF) of Australia recommends lifestyle advice supplemented by pharmacological measures for the appropriate management of hyperlipidemia.17 Management should be based on both the individual’s measured serum cholesterol levels and estimated absolute cardiovascular risk. The management aims to lower the plasma lipid levels as part of the absolute risk profile of the individual, which is particularly relevant in high-risk groups such as diabetics, people with familial hypercholesterolemia, vascular disease, chronic kidney disease and those with a family history of coronary heart disease.17

Table 18.1 summarises the NHF recommendation of lifestyle factors for reducing cholesterol levels and risk of developing cardiovascular disease.

Table 18.1 NHF recommendation of lifestyle factors17

Dietary advice

Exercise — be physically active; at least 30 minutes of moderate-intensity daily Maintain a healthy weight Avoidance of smoking; being smoke-free

Table 18.2 summarises the NHF recommendations for drug and nutrient therapy in patients with hyperlipidemia.

Table 18.2 NHF recommendations of drug/nutrient therapy17

Statins (HMG-CoA Reductase Inhibitors) Reduces the level of LDL-C; modest triglyceride-lowering; HDL-C-raising effects
Fibrates
Fish oils  
Bile acid binding resins in selected patients  

The NHF goals and targets for therapy, especially in people with existing coronary heart disease or other high-risk groups, are summarised as:17

Lipid management recommendations, if adopted, have immense potential for significant health gain; however conventional lipid-modifying treatments such as statins and fibrates are underused, due to both under-prescription and non-adherence to treatment in Australia and overseas.18, 19 The Adult Treatment Panel III (ATP III) guidelines of the US National Cholesterol Education Program (NCEP) emphasise the importance on lowering cholesterol but also place greater emphasis on lowering triglyceride levels.20 Therefore statin monotherapy may not be sufficient to achieve the recommended non-LDL goals, especially given their modest effects on triglyceride concentration.

Pharmacological therapies including bile acid sequestrant resins, statins, fibrates, niacin and cholesterol absorption inhibitors are common treatment options for hyperlipidemia, however the use of alternative therapies is also becoming increasingly popular. Controlled trials using a range of dietary supplements, herbal extracts and functional foods (e.g. policosanols, flaxseed, red yeast rice, guggulipid, garlic, viscous fibre, tree nuts and soy proteins) have been examined as potential complementary treatments in the management of hyperlipidemia.21 A recent survey found that as many as 50% of respondents with elevated cholesterol levels would prefer non-prescription drugs such as garlic, yeast, or soy products as an alternative to pharmaceutical drugs.22

This chapter reviews the data from human clinical trials that have studied the efficacy of lifestyle changes, pharmaceutical and complementary medicines (CMs) to treat lipid aberrations. The discussion on CMs is limited to hyperlipidemias and will not encompass relationship with cardiovascular disease. Evidence for the complementary and synergistic efficacy of the combined pharmaceutical and alternative therapies is also presented.

Risk factors for hyperlipidemia

Risk factors for hyperlipidemia include:

Familial hypercholesterolemia

Familial hypercholesterolemia (FH) is caused by a defect on the short arm of chromosome 19 via an autosomal dominant gene.23 FH is a result of mutations that influence the binding of LDL particles to the cell-surface receptor (LDL-receptor). Five classes of mutations in the LDL-receptor have been identified with each class having multiple alleles.24 Class 1 mutations are null mutations as these result in a complete failure to express any LDL-receptor protein. Most common are the class 2 mutations resulting in intracellular transport defects so that the LDL-receptor does not move between the intracellular membranes (endoplasmic reticulum and the golgi membranes). Class 3 mutations involve LDL-receptors that are expressed and transported to the cell surface but fail to bind with LDL particles. Class 4 mutations are the rarest that result in failure of the LDL-receptor/LDL particle complexes be internalised. Class 5 mutations cause failure of the LDL-receptor recycling back to the cell surface. Regardless of the class of mutation, the body’s ability to remove LDL-cholesterol from the bloodstream is impaired and that results in raised blood levels of LDL-cholesterol, contributing to increased risk of atherosclerosis, cardiovascular and coronary heart disease.

Pharmaceutical treatment of hyperlipidemia: key factors to consider

Adverse health effects

Although statins are generally well tolerated, many clinicians believe that, in practice, statin-related side-effects occur more commonly than reported in randomised trials. Recently, researchers identified a common variant of a gene on chromosome 12 that predisposes patients to statin myopathy.27 Another point of controversy is whether statins cause cognitive problems in some people. Yet another concern about statins and cognition was raised in a recently published Canadian study in which the researchers used a national database to conduct a retrospective analysis of nearly 300 000 patients who had undergone elective surgery. Patients who had been prescribed statins during the previous 90 days had a significantly higher risk for developing post-operative delirium than did statin non-users. Intriguingly, no other class of cardiovascular drugs was associated with postoperative delirium. The authors speculated that altered cerebral blood flow, resulting from the effects of statins on vascular smooth muscle, could be 1 mechanism for statin-induced post-operative delirium. The beneficial effects of statins in high-risk patient populations are indisputable. However, these drugs increasingly are being prescribed to asymptomatic people on the basis of somewhat arbitrary serum lipid thresholds, without regard to overall cardiovascular risk.

The most common adverse reactions associated with the use of statins are myopathy, muscle pain and weakness, which are reversible upon cessation of the statins. However, if severe, statins can cause rhabdomyolysis, severe myopathy and hepatitis in sensitive individuals.

Lifestyle factors

Diet and exercise, apart from genetic predisposition, are the most important factors contributing to the development of hyperlipidemia, and should be considered as the primary management of hyperlipidemia.

Stress management

A number of studies have demonstrated the possible link between stress and hyperlipidaemia. With prolonged stress, the pituitary-adrenal cortical system is activated to secrete cortisol. This is lipogenic and the plasma cholesterol levels can rise up to 60% above baseline.28, 29 An American study including a survey of 187 394 respondents from the Behavioural Risk Factor Surveillance System (BRFSS), aged 35 years or older from 37 states and territories, confirmed the linear relationship between psychological distress and blood cholesterol.30 However, whether stress is the cause or consequence of increased blood cholesterol or whether it is a casual relationship remains unclear. A recent study, in which participants were asked to increase dietary fibre intake to >30g/day; reduce saturated fat intake to <16g/day; trained to reach 70-85% of their maximum heart rate; perform strength training for 3 days/week and engage in 10-20 minutes of stress management activities daily, demonstrated a reduction in the ratio of total to HDL-cholesterol by 8.9% and plasma cholesterol lowering by 7.3%.31

Randomised controlled trials (RCTs) involving specific intervention with stress management alone are required to delineate further the relationship between blood lipids and stress.

Yoga

Yoga has become increasingly popular in Western cultures as a means of exercise and training fitness. It has been used clinically as a therapeutic intervention and its practice includes muscle stretching, breathing exercises, behavioural modification, and dietary control through mental discipline. An Indian RCT examined the effects of yoga and meditation on biochemical parameters of metabolic syndrome.32 In this study, 101 participants were randomised to receive either the usual care (n = 46) or yogic intervention in addition to usual care for 3 months (n = 55). At the end of the intervention period, plasma triglyceride levels decreased from 210 to 152mg/dL and HDL-cholesterol increased from 33.4 to 44.5mg/dL in the group receiving yogic intervention.

Physical activity and exercise

A 5-year follow-up study of more than 7000 men with average age of 66, demonstrated that physical activity was associated with positive changes to lipid profile.33 Cross-sectional and longitudinal exercise training studies indicate that 15 to 20 miles/week of brisk walking or jogging, which elicit between 5000 to 9000 kilojoules of energy expenditure per week, is associated with triglyceride lowering from 5 up to 38mg/dL and HDL-cholesterol increases of 2 to 8mg/dL. Halverstadt et al.34 showed that endurance exercise training induced favourable changes in plasma lipoprotein and lipid profiles independent of diet and baseline or change in body fat. Another small study involving 12 healthy unfit men and women, subjected to 6 weeks of exercise, demonstrated that endurance training results in a decrease of LDL-cholesterol by 21%, apoB levels by 19% and an increase in HDL-cholesterol by 10%.35 Exercise training rarely alters serum cholesterol or LDL-cholesterol unless dietary fat intake is reduced and body weight loss is associated with the exercise training program, or both. The decrease in plasma triglyceride concentrations is related to baseline concentrations36, 37, 38 with greater reductions in people, previously inactive and higher baseline concentrations.37, 39, 40, 41 Resistance training, however, appears to have no effects on blood lipids, even when initial blood lipid levels are elevated.4246 A recent Portuguese study compared the effects of 2 exercise programs of 8 months duration on lipid profiles in older women.47 Women (n = 77) aged 60-79 years were randomly assigned to either a multi-component exercise program or resistance exercise program. Significant decreases in plasma triglyceride (−5.1%), and significant increases in HDL-cholesterol (9.3%) were observed in the multi-component exercise group while no significant changes in lipid profile were observed in the resistance exercise group.47

Only a small number of studies have investigated the effects of physical activity on blood lipids and lipoproteins in a race- and sex-specific manner. African American and white participants of the Atherosclerosis Risk in Communities (ARIC) study were investigated for the longitudinal effects of physical activity on plasma lipids and lipoproteins.48 Nine years of follow up data on 8764 individuals aged 45-64 years at baseline demonstrated that increases in the level of activity were associated with increases in HDL and decreases in triglycerides among white participants. Physical activity was associated with reduced LDL in all women, while the association with total cholesterol was limited to African American women.

Nutritional influences

Diet

Diet plays the most important role in the management of hyperlipidemia.

Low (saturated) fat — epidemiological studies

A wealth of epidemiological and interventional studies over the last 60 years has established a link between saturated fat intake and serum cholesterol levels. Perhaps the most quoted of these is the Seven Countries Study,49 in which the dietary habits of 12 763 middle-aged men comprising 16 cohorts from 7 countries were studied, and the relationship to serum cholesterol and coronary disease mortality analysed over subsequent years. This study was carried out between 1958 and 1964, with the information on dietary intake collected by the dietary record method. It allowed inter-cohort comparisons to be made, but analysis on an individual level was not possible. Large variations were seen in the average intake of different saturated fats, and correlations were found between the intake of lauric and myrisitic acids and serum cholesterol increases. In the Western Electric Study,50 1900 middle-aged men randomly chosen from the Western Electric Company’s Hawthorne Works in the Chicago area were analysed for their dietary intake, and serum cholesterol concentrations were measured. The information was collected through interviews and questionnaires by nutritionists. Again, a positive correlation was apparent between serum cholesterol and saturated fat intake. In Belgium, an epidemiological analysis was performed on the differences between the dietary intakes of Belgians living in the north and south of the country.51 Food intake was gathered through 3 independent sources: an investigation of 451 families in the north and 752 in the south, a survey by the Ministry of Agriculture, and through the Ministry of Economic Affairs by way of the National Institute of Statistics. This information revealed a much higher intake of saturated fat in the south compared to the north, and also a lower intake of total polyunsaturated fats in the south. Evidence gathered over 10 years revealed decreasing average serum cholesterol in the north of the country, and a higher serum cholesterol in the south, allowing the authors to conclude a positive relationship between saturated fat intake and serum cholesterol. Kato et al.52 undertook a large scale study of men of Japanese ancestry living in 3 different environments, which was a useful approach as it limited the effects of genetic influences on serum cholesterol changes. Information was collected by 24-hour recall dietary interviews. Dietary intake patterns varied markedly between the men in Japan, Hawaii and California, with serum cholesterol levels showing an apparent positive regression with saturated fat intake.

Low (saturated) fat — interventional studies

Along with epidemiological evidence, there have been a number of interventional studies attempting to establish the link between saturated fat intake and serum cholesterol. Keys et al.53 in 1957 used 66 middle-aged schizophrenic men for a dietary experiment to establish a link between fat intake and serum cholesterol. On a fixed calorie diet, the type of fat fed to the subjects was varied, with 2–9 weeks spent on each experimental diet. The fats used were butter fat, hydrogenated coconut oil, olive oil, cotton-seed oil, corn oil, sunflower-seed oil, safflower oil and fish oil. The percentage of the caloric intake from saturated, monoethenoid and polyethenoid fats were estimated, and serum cholesterol was measured in duplicate at the end of each dietary period. The authors came to the conclusion from their results that saturated fatty acids (especially fats containing 10 or more carbons) such as butter fat and coconut oil have about twice the effect in raising total serum cholesterol as the cholesterol depressing effect of equal amounts of polyethenoid fats. Another major study often used as apparent evidence is that of Hegsted et al.54 Two groups of 10 normocholesterolaemic male subjects were tested whilst being fed diets with fixed fat (38% caloric intake) and protein proportions, with carbohydrates varied to make caloric intake appropriate for each subject. Each test period lasted for 4 weeks, with the type of fat varied (coconut, olive, safflower). Samples taken were measured for total serum cholesterol, beta-lipoprotein cholesterol, total fatty acids, and lipid phosphorus. It was concluded that myristic acid is most hypercholesterolemic. Another highly referenced article on the saturated fat theory is that of Ahrens et al.,55 who examined 40 patients who were either hyperlipidaemic, hypercholesterolaemic or normocholesterolaemic with arteriosclerotic heart disease. The subjects were observed for 4–6 months under controlled dietary conditions, with fixed calories, total fat (40% of total calories), carbohydrates and proteins. The type of fat fed to the subjects varied between corn oil and coconut oil. Serum cholesterol levels were found to be higher on the coconut oil diet (high in saturated fat) and lower on the corn oil diet (high in polyunsaturated fat). Shepherd et al.56 studied the effect of dietary fatty acids on low density lipoprotein (LDL) in 8 young normocholesterolaemic adult males. During study 1, the subjects received a diet rich in saturated fat, derived mainly from dairy products. In study 2, the fat intake from the dairy products was replaced by safflower oil, lower in saturated fat and higher in polyunsaturated fats. Both diets were controlled for total caloric intake and dietary cholesterol. Serum samples were measured for triglyceride, plasma cholesterol, and lipoprotein cholesterol concentrations. It was concluded that compared to the saturated fat diet, the polyunsaturated diet lowered both plasma cholesterol and triglyceride, with 67% of the cholesterol reduction due to a fall in LDL-cholesterol. Similar results were seen by Turner et al.,57 where 15 subjects (7 normal and 8 with type II hyperlipoproteinaemia) were fed diets with 40% calories as either safflower oil or lard. The diets were chosen to maximise the difference in the degree of saturation of the dietary fat whilst maintaining constant cholesterol and total fat intake.

A strict, very low saturated fat, low cholesterol American Heart Association Step 2 diet only minimally lowers serum cholesterol. A 5% reduction in LDL-cholesterol in patients following this program was reported and, discouragingly, an equivalent 6% fall in HDL-cholesterol, so that ratios were unchanged.58 Low-fat diets as commonly prescribed rarely produce significant LDL declines. Studies performed on controlled metabolic units where intakes are rigidly enforced can demonstrate cholesterol reductions of 15% with diet alone; however, in the real world, people can rarely replicate these results.59 One exception to this, however, is the Dean Ornish-style diet, which was studied in the Lifestyle Heart Trial.60 This vegetarian diet consists of fruits, vegetables, soybean products, non-fat milk, and yoghurt with no oils or animal fats. Roughly 7% of calories are from fat, 15% to 20% from protein, and the remainder from complex carbohydrates. Only 12mg of cholesterol per day is allowed. On average, Ornish’s patients had a 37% reduction in LDL-cholesterol levels (HDL-cholesterol levels were unchanged).

What is most provocative about this diet/lifestyle program is that there was a 91% reduction in angina frequency and a significant degree of angiographically measured coronary stenosis regression. It is unclear to what degree other lifestyle modifications, such as exercise and stress reduction, which are integral parts of the Ornish program, play in these results. The problem with the Ornish diet is that it is so stringent that most Americans find adhering to it nearly impossible. In addition, critics of this study note that it had only 48 subjects; thus, the outcome should be viewed sceptically until larger trials are completed. The greatest scientific objection to the Ornish-style diet is that it is now known that high-carbohydrate, low-fat diets raise triglyceride levels, lower HDL levels, and may convert LDL lipoproteins into smaller, denser, and more atherogenic particles.61 Nevertheless, the Ornish diet provides the greatest absolute LDL reduction available by diet alone and is of a magnitude similar to that of high-dose statin therapy, which can reduce cholesterol by 25% to 60% depending upon the drug dose.62 A recent meta-analysis of 60 controlled trials revealed that as the chain length of the saturated fatty acids increase, their cholesterol-raising effects tapers off. Accordingly, lauric acid (C12:0) is most hypercholesterolemic and the longer chain stearic acid (C18:0) in fact is cholesterol neutral or even slightly hypocholesterolemic.63 Based on the above evidence, most international dietary guidelines recommend that total fat intake should be limited to 30% of daily energy intake with saturated fat contributing no more than 10% of daily energy intake to control blood lipid levels. Families with high cardiovascular risk factors such as familial hypercholesterolemia may also warrant for children to be on a diet low in saturated fats and cholesterol. Researchers demonstrated a diet low in saturated fats (30–35% of daily energy) and cholesterol (less than 200mg/day) in early children, aged 7 months to 5 years, reduced cholesterol levels by 3–5% compared with controls without affecting development which may reduce the risk of cardiovascular disease in adulthood.64 The authors warned against over-restricting dietary fat intake in young children.

Monounsaturated fats

A large majority of the published literature suggests that consumption of monounsaturated fatty acids (MUFA), primarily oleic acid rich sources including olive oil, high oleic safflower oil, canola oil, sunola (genetically modified sunflower) oil, macadamia oil and avocado oil, are cholesterol neutral; that is, they do not significantly affect plasma cholesterol. Therefore, not surprisingly, MUFA consumption is not factored in any of the equations used to predict the change in blood cholesterol levels such as those put forward by Hegsted et al.54 and Keys.65 Intervention studies involving 24–28% of daily energy in the form of MUFA conducted in the 1980s reported reduction in LDL-cholesterol to the same extent to that of a low fat, high-carbohydrate diet.66

Monounsaturated fats and the Mediterranean diet

More widely studied and perhaps more practical for the treatment of patients with coronary artery disease is the Mediterranean diet rich in MUFA. In the 1950s, Ancel Keys began studying the dietary habits of 1770 inhabitants of various countries and correlating them with subsequent mortality.67 His landmark study found that the mortality rates from heart disease were 2–3 times lower in the countries bordering the Mediterranean Sea compared with Northern Europe and the USA. Notably, studies conducted in North America, where MUFA source was not olive oil but other plant or animal oils, failed to demonstrate benefits of MUFA-rich diets, raising possibilities of benefits of Mediterranean diet components other than MUFA. Another potential mechanism is that a diet rich in fruits and legumes provides folic acid, which may reduce cardiac risk by lowering plasma homocysteine.68 Also, moderate alcohol consumption is associated with decreased cardiovascular risk, in part by increasing HDL levels,69 and both red wine and some Mediterranean plant foods contain large amounts of flavonoids, which are natural antioxidants and antithrombotic substances.70 But the most provocative explanation is that the Mediterranean diet contains α-linolenic acid which is an omega-3 fatty acid and has been shown to possess antithrombotic properties and may also be antiarrhythmic.71, 72 This α-linolenic acid is a precursor of other omega-3 fatty acids found in fish and fish oil, such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), which may have independent beneficial effects that are discussed later in this review.

Nevertheless, based on the reported studies, Adult Treatment Panel III (ATP-III) recommended that human diets should contain at least 15% energy from MUFA for optimisation of blood cholesterol levels.

Polyunsaturated fats

Most polyunsaturated fatty acids in the diet belong to the omega-6 (mainly linoleic acid) family, present in large amounts in seed oils such as corn, sunflower, soybean and cottonseed. Consumption of these has been shown to lower serum cholesterol, LDL-cholesterol and, in clinical trials, the risk of heart disease. Every 1 gram increase in linoleic acid consumption resulted in plasma cholesterol lowering by 1mg/dL.73 Increased consumption of linoleic acid may induce increased expression of hepatic LDL-receptors, thereby enhancing increased LDL uptake in the liver for further metabolism.74

Controversy surrounds omega-6 polyunsaturated fatty acids, because even though they lower LDL-cholesterol levels, excessive intakes do not appear to be correlated with cardiovascular benefit.75 Recently, Jakobsen et al.76 pooled data on diet and the incidence of heart disease in 340 000 people from the United States, Scandinavia, and Israel. Metabolic trials of diet and blood lipids show that replacing 5% of energy from saturated fatty acids with polyunsaturated fatty acids reduces the serum total/HDL-cholesterol ratio by 0.17.77 In prospective observational studies, such a reduction in the total-to-HDL-cholesterol ratio is associated with a reduction in heart disease risk of 9%.78 The effect of omega-6 fatty acids on blood lipids, combined with prospective data on blood lipids and heart disease, predicts a 9% risk reduction. The randomised clinical trials predict an 8% reduction, and the observational studies pooled by Jakobsen et al.76 predicted a 13% reduction for people who eat 5% of calories as polyunsaturated instead of saturated fatty acids.

Based on the information in the literature, The American Adult Treatment Panel III (ATP-III) recommended that 10% of daily energy will make an optimal intake of polyunsaturated fatty acids, of which at least 1% of total energy should originate from omega-3 fatty acids for control of blood lipid profiles.

Tree nuts

Nuts are energy-rich foods and are an excellent source of unsaturated fatty acids. The favourable fatty acid profile perhaps contributes to the health benefits of nuts observed in epidemiologic studies and cholesterol-lowering potential in feeding trials.79, 80 Besides, the nuts contain many bioactive compounds such as vegetable protein, fibre, minerals, vitamin E, and polyphenols.81 RCTs involving dietary supplementation with peanuts, walnuts, pistachio nuts, almonds, hazelnuts and macadamia nuts have demonstrated a reduction in serum total cholesterol and LDL-cholesterol.

A systematic review of studies investigating independent effects of nuts show reduction in total cholesterol between 2–16% and LDL-cholesterol between 2–19% in subjects consuming almonds or walnuts or pecan nuts or peanuts or macadamia nuts compared with those consuming control diets.79 Another review of clinical studies concluded that tree nuts lower LDL-cholesterol by 3–19% compared with Western and lower-fat diets.80 In summary, nuts as part of a healthy diet can play an important role in maintenance of blood cholesterol levels. Of all the nuts, walnut is the most extensively studied tree nut and appears to possess hypocholesterolemic properties. A recent crossover randomised control trial in which 25 normal or mildly hypercholesterolemic subjects were supplemented with 42.5g of walnuts daily for 4 weeks, confirmed serum cholesterol reduction of 9.5% and LDL-cholesterol reduction of 5.2%.82

High-protein diets

One of the initial concerns with the high-protein diets for weight loss, such as the Atkins diet, was that it allows unrestricted fat consumption, including saturated fats known to increase total and LDL-cholesterol. When the Atkins diet was studied by Samaha83 in comparison to a low-fat diet (16% fat) in severely obese subjects, they found that the high-protein diet significantly lowered triacylglycerol (TGL) by 20% versus 4% in the low-fat group (p = 0.001). The Atkins diet was also tested in a study by Foster,84 where at 3 months a significant reduction in LDL-cholesterol and triglyceride and a significant increase in HDL-cholesterol were found, compared to a low-fat diet group. Changes in LDL-cholesterol were not maintained at 1 year, therefore significant differences between the groups was lost. In view of the fact that adherence to the diet was very poor, the relevance of this is not yet clear.

Other studies85, 86 demonstrated significant reductions in triglyceride and oxidised LDL-cholesterol, with high-protein diets. By contrast, Parkers study87 in 54 type-2 diabetics on a high-protein diet (30% protein) compared to a high-carbohydrate group (15% protein), did not find any significant changes in triglyceride. Findings in regards to both LDL-cholesterol and HDL-cholesterol are even more varied. In a systematic review on low-carbohydrate diets, Bravata88 found that no change was detected overall in any serum lipids. They note that the studies were few in number and there was a wide variety in the design. However, from limited evidence, it does appear that higher protein diets do not have any adverse effects on total and LDL-cholesterol, though their effect on HDL-cholesterol is less clear. While more research is needed in these areas, it appears that moderately high-protein diets are not harmful to cardiovascular health and may indeed be beneficial.

A dietary portfolio for hyperlipidemia

Efforts to lower cholesterol through dietary manipulations have had only modest effects. In an attempt to increase the efficacy of diet in the prevention of cardiovascular disease, the Adult Treatment Panel of the National Cholesterol Education Program has recommended adding plant sterols and viscous fibres to the diet.20 Soy proteins and tree nuts may have additional health benefits. Jenkins and colleagues examined the cholesterol-lowering potential of a diet low in saturated-fat that included these ingredients.90 Forty-six hyperlipidemic, otherwise healthy subjects completed the 4-week study. After 4 weeks of following their own diet that was low in saturated fat, participants were randomised into 1 of the following groups: a very-low-saturated-fat diet without a statin control group; the same diet with a statin; or a similar diet with added viscous fibres, plant sterols, soy foods, and almonds (portfolio diet).

After 4 weeks, the control group lowered their LDL-cholesterol by 8% and increased the LDL-cholesterol to HDL-cholesterol ratio by 3%. The group receiving a statin lowered their LDL-cholesterol by 30.9% and decreased the LDL-cholesterol to HDL-cholesterol ratio by 28.4%. The portfolio diet group lowered their LDL-cholesterol by 28.6% and decreased the LDL-cholesterol to HDL-cholesterol ratio by 23.5%. Clearly the reductions in blood lipid levels in the statin and portfolio diet groups were considerably greater than the changes in the control group; however, no significant differences were apparent in the statin versus the portfolio diet groups. The authors concluded that diet alone, if selecting for foods with a combination of cholesterol-lowering properties, can lower cholesterol to the same extent as statins.90 Compliance in all the 3 groups was reported to be 93%. These results were subsequently confirmed by another similar study.91 The long-term sustainability of clinically meaningful reduction in LDL-cholesterol of >20% by dietary means in motivated individuals has also been reported.92

Additional benefits of a portfolio diet include weight loss,92, 93 reduced blood pressure,93 and reduced inflammation as indicated by a reduction in CRP levels.90, 94 It has also been shown that the reduction in serum cholesterol following the consumption of the portfolio diet is attributable to decrease in the level of the highly atherogenic, smallest subclass of LDL.95 More importantly, these health benefits can be achieved without side-effects. Notably the portfolio diet had no effect on the HDL-cholesterol or triglyceride levels. Long-chain omega-3 fatty acids, particularly docosahexanoic acid (DHA), is known to decrease triglyceride and increase HDL-cholesterol levels, therefore, addition of DHA may enhance the lipid-lowering potential of the portfolio diet.

Alcohol

Moderate alcohol consumption is associated with decreased cardiovascular risk in part by increasing HDL levels.69 Red wine, rich in flavonoids, a natural antioxidant with antithrombotic properties, is particularly more beneficial.70

Grapefruit juice

Israeli grapefruit juice, with a high level of bioactive compounds, has been shown to possess cholesterol-lowering properties. An RCT of 72 hypercholesterolemic patients were divided into either a control group or experimental groups supplemented daily with 100 or 200 mL of fresh grapefruit juice for 30 days.96 Following the intervention period, total cholesterol decreased by 9.5%, and 16.1%; LDL-cholesterol by 11.6% and 21.0%; and triglycerides by 11.5%, and 24.7% in the groups supplemented with 100mL and 200 mL of grapefruit juice respectively. In a follow-up study by the same authors,97 the lipid-lowering potential of red versus blonde grapefruit was compared. Fifty-seven hypercholesterolemic patients, after coronary bypass surgery, were divided into either a control group or experimental groups supplemented daily with 1 equal weight of red or blond grapefruit. Following the 30-day intervention period, total cholesterol decreased by 15.5%, and 7.6%; LDL-cholesterol by 20.3% and 10.7%; and triglycerides by 17.2%, and 5.6% in the red and blond grapefruit fed groups respectively.97 It is conceivable that addition of grapefruit (especially red variety) juice may be beneficial for hypercholesterolemic individuals in a dose-dependent manner. The magnitude of the lipid-lowering following red grapefruit consumption should prompt further interest in this food as part of a healthy diet.

However, care is required as grapefruit juice is known to interact and augment the drug bioavailability with many pharmaceutical drugs. (See chapter on Herb-drug interactions). The mechanism for this interaction is via the inhibition of cytochrome P-450 3A4 in the small intestine, reducing the metabolism of the drug, and also the inhibition of P-glycoprotein resulting in further increases in absorption of the drug, potentially leading toxic levels.98 Drugs metabolised by the pathways that are most affected by grapefruit juice include some calcium channel antagonists (e.g. nifedipine, verapamil), blood thinning medications such as warfarin (increasing risk of bleeding), benzodiazepines (e.g. midazolam and diazepam increasing risk of sedation), HMG-CoA reductase inhibitors/statins (increasing risk of side-effects such as myopathies) and cyclosporine. Even a single glass of juice can produce a significant interaction.99

Soybean products

Soybean-derived protein has been shown to possess considerable cholesterol-lowering potential in clinical studies involving hypercholesterolemic subjects. In 1995, a meta-analysis concluded that partial or full replacement of dietary animal proteins by soy protein resulted in an average reduction of 23mg/dL in plasma total and 22mg/dL in LDL-cholesterol concentrations.100 The observed effects of soybeans on plasma lipids were not extended to triglycerides or HDL-cholesterol. Moreover, reductions in plasma cholesterol were dependent on baseline levels with greater reductions noted in subjects with established hypercholesterolemia.100 Another recent meta-analysis confirmed these effects of soy proteins.101 It has been shown that the cholesterol-lowering ability of soy proteins may be attributed to its ability to up-regulate apo-B receptor gene expression.102, 103

Another component of soybeans, isoflavones, structurally similar to oestrogen, have been examined for their cholesterol-lowering potential. Isolated soy isoflavones introduced in amounts from 28–150mg have achieved statistically insignificant reductions in LDL-cholesterol in the range of 1–6.5%.104 These minor declines in non-HDL/LDL-cholesterol concentrations would be of little clinical significance in terms of a reduction in the risk of developing coronary artery disease, but when combined with dietary changes may have an additive beneficial effect.

Based on the published scientific evidence, the United States Food & Drug Administration issued a health claim that 25g/day of soy protein, when supplemented in the diet may significantly reduce the risk of cardiovascular disease via an average fall of up to 10% in plasma cholesterol levels, depending on initial values.105

Nutritional supplements

Phytosterols

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