Nutrition, Nutritional Supplements, and Drugs in the Management of Dyslipidemia
Mark C. Houston, MD, MS, MSc, FACP, FAHA, FASH, FACN, FAARM, ABAARM, DABC
Sergio Fazio, MD, PhD
Brief Summary
The combination of a lipid-lowering diet and scientifically proven nutritional supplements and drugs has the ability to significantly reduce total cholesterol (TC) and low-density lipoprotein (LDL) cholesterol (LDL-C) levels; decrease LDL particle concentration (LDL-P); increase LDL particle size; lower triglycerides (TG), remnant particles, very-low-density lipoprotein (VLDL), and lipoprotein (a) levels; increase total high-density lipoprotein (HDL) cholesterol (HDL-C) and HDL particle concentration (HDL-P); provide beneficial effects on HDL subfractions; and improve HDL functionality. In addition, inflammation, oxidative stress, and abnormal vascular immune responses are decreased as a result of these interventions. In several prospective clinical trials, coronary heart disease (CHD) rates have been reduced with optimal nutrition and/or administration of several nutritional supplements, including omega-3 fatty acids (FAs), red yeast rice (RYR), alpha-linolenic acid (ALA), berberine, and niacin. Other studies have shown additional reduction in CHD events using a statin with an omega-2 FA and with drugs such as ezetimibe and monoclonal antibodies against PCSK9. An integrative program of nutrition, nutritional supplements, and lipid-lowering drugs represents the most scientifically valid and most efficacious approach for the treatment of dyslipidemia. This new approach to decrease dyslipidemia-induced vascular disease goes beyond the present traditional evaluation and management of an altered standard lipid panel or even advanced lipid testing with particle number and particle size, to the recognition and treatment of the multiple mechanisms that are secondary to or synergistic with dyslipidemia in the development of atherosclerosis and CHD.
Introduction
The combination of a lipid-lowering diet with the judicious use of scientifically proven nutritional supplements and lipid-lowering drugs has the ability to significantly reduce TC and LDL-C; decrease LDL particle number (LDL-P); increase LDL particle (LDL-P) size; lower TG, remnant particles, VLDL, and lipoprotein (a) levels; and increase HDL-C and HDL particle number (HDL-P), while providing a beneficial effect on HDL subfractions and HDL functionality. In addition, vascular inflammation, oxidative stress, and vascular immune responses are also decreased with aggressive lipid management. In several prospective clinical trials, CHD, myocardial infarction (MI), and cardiovascular disease (CVD) events have been reduced by nutraceutical supplements utilized. Other trials show additional improvement in CHD events when lipid-lowering drugs such as statins are supplemented with nutraceuticals such as omega-3 FAs or niacin. This chapter will review the role of nutrition, nutritional supplements, and lipid-lowering drugs that favorably improve dyslipidemia and address the myriad steps and mechanisms involved in lipid-mediated atherosclerosis and clinical cardiovascular events such as MI and stroke.
Pathophysiology
Dyslipidemia is a major risk factor for CHD, along with hypertension, diabetes mellitus (DM), smoking, and obesity.1 The mechanisms by which certain plasma lipids induce vascular damage are complex, but from a pathophysiologic viewpoint these include vascular inflammation, oxidative stress with reduced oxidative defense, and vascular immune dysfunction.2,3,4 These pathophysiologic mechanisms lead to endothelial dysfunction (ED) and vascular smooth muscle
dysfunction (VSMD) with loss of arterial elasticity and compliance. In addition, coronary artery obstruction, coronary artery ED, and coronary artery spasm cause cardiac myocyte dysfunction. The consequences are CHD, MI, and cerebrovascular accidents (CVAs).4
dysfunction (VSMD) with loss of arterial elasticity and compliance. In addition, coronary artery obstruction, coronary artery ED, and coronary artery spasm cause cardiac myocyte dysfunction. The consequences are CHD, MI, and cerebrovascular accidents (CVAs).4
The causes of dyslipidemia include genetic inheritance and a number of acquired conditions such as poor nutrition, visceral obesity, numerous comorbidities, and the use of pharmacological agents such as nonselective and nonvasodilating beta blockers and diuretics (including hydrochlorothiazide and chlorthalidone), anti-retrovirals, retinoids and rexinoids, steroids, and sex hormones.5 In addition, tobacco use, DM, hypothyroidism and other metabolic dysfunctions, an abnormal gut microbiome, acute and chronic infections, heavy metals, toxins, and lack of exercise also may induce dyslipidemia.5 Often there are both genetic and acquired factors at play. For example, several genetic phenotypes, such as the common apolipoprotein E (apoE) polymorphism, regulate intestinal absorption of dietary fat and result in variable serum lipid responses to diet, thus controlling the risk for CHD and MI.6,7 In addition, variations in the HDL proteome, involving players such as paroxonase-1 (PON-1), scavenger receptor B-1 (SR -BI), SCARB-1, and apolipoprotein C3 (APO C3), influence the risk for CHD and MI.8 The Sortilin I allele variants on Chromosome 1p13 increase LDL-C and CHD risk by 29%.9 More recently, a polygenic risk score has been developed to identify common variants in a number of genes modulating lipid metabolism in a single individual. An elevated risk score explains many cases of familial hypercholesterolemia not due to mutations in the LDL receptor.10
Recent studies suggest that dietary cholesterol intake has a minimal effect on serum cholesterol levels and on rates of CHD and MI, and that only saturated fats (SFAs) with a carbon length of C12 or greater have adverse effects on serum lipids and CHD risk.5,11,12,13,14,15,16,17 However, consumption of monounsaturated (MUFAs) and polyunsaturated fats (PUFAs) has a favorable influence on serum lipids and CHD risk. Increased refined carbohydrate intake adversely affects serum lipoproteins and their subfractions more than do short-chain SFAs with carbon length of C-10 and less. Refined carbohydrates and sugars have significant effects on insulin resistance and adverse effects on LDL-C, LDL-P, LDL-P size, VLDL, TG, total HDL-C, HDL-P, HDL subfractions, HDL functionality, vascular inflammation, oxidative stress, and vascular immune function. All of these lipid changes from sugar intake contribute more to CHD risk than do short-chain SFAs.5,11,12,13,14,15,16,17
 Figure 22.1 The various lipoprotein particles are shown with nuclear magnetic resonance (NMR). High-density lipoprotein (HDL), low-density lipoprotein (LDL), intermediate-density lipoprotein (IDL), very-low-density lipoprotein (VLDL), and chylomicrons. |
The validity of the long-standing “Diet Heart Hypothesis,” which suggests that dietary SFAs and dietary cholesterol increase the risk of CHD and MI has been questioned.12,13,14 However, dietary trans fatty acids (TFAs) do have definite adverse lipid effects and increase the risk of sudden death, MI, CVD, and CHD. The TFAs suppress transforming growth factor beta responsiveness, and this facilitates the deposition of cholesterol in vascular tissue.12,14,15,16 In contrast, PUFAs and omega-3 FAs, such as docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), and MUFAs improve serum lipids and reduce CHD and MI risk.5,11,12,13,14,15,16,17
Expanded lipid profiles (advanced lipid testing) that measure lipids, lipid subfractions, particle size, particle number, and apolipoprotein B and A are preferred over the standard lipid panel that measures only the TC, LDL-C, TG, and HDL-C (Figure 22.1). Expanded lipid profiles are offered by numerous commercial laboratories, including Boston Labs, Berkeley Labs, LabCorps, and Quest Diagnostics. These expanded lipid profiles have been shown to improve CHD risk profiling, better predict CHD and MI events, and allow a more accurate assessment of the lipid changes that occur with exercise, weight loss or weight gain, lifestyle changes, and use of nutritional supplements or pharmacotherapy.18,19 CHD risk assessment, identification of the mechanisms of dyslipidemia-induced vascular disease, and evaluation of efficacy of natural or drug treatment are vastly improved
by using the new expanded lipid profiles.18,19 In addition, new concepts in assessing dysfunctional or inflammatory HDL-C20 directly or indirectly by measuring reverse cholesterol transport,21 lipoprotein-associated phospholipase A2, platelet-activating factor acetylhydrolase, high-sensitivity C-reactive protein (hsCRP), and myeloperoxidase levels22 will add to the intervention toolkit and allow improved assessment of CHD and MI risk.
by using the new expanded lipid profiles.18,19 In addition, new concepts in assessing dysfunctional or inflammatory HDL-C20 directly or indirectly by measuring reverse cholesterol transport,21 lipoprotein-associated phospholipase A2, platelet-activating factor acetylhydrolase, high-sensitivity C-reactive protein (hsCRP), and myeloperoxidase levels22 will add to the intervention toolkit and allow improved assessment of CHD and MI risk.
An understanding of the pathophysiological steps and mechanisms in dyslipidemia-induced vascular damage and atheroma plaque formation that goes beyond measurement of lipid levels or even expanded lipid profiles allows for the treatment of dyslipidemia and prevention of CHD and MI to be conducted in a more logical and efficacious manner (Figure 22.2). The ability to interfere with most steps and mechanisms in this pathway will allow more specific approaches and treatments to reduce vascular injury, improve vascular repair systems, and maintain and restore vascular health. Native LDL, especially large type A LDL, is not usually atherogenic unless it accumulates in very high concentrations or is oxidized or otherwise modified. However, effective pinocytosis mechanisms allow macrophage ingestion of native LDL-C in the setting of chronic infection or inflammation, which could account for up to 30% of the foam cell formation in the subendothelium.23,24 Identifying maneuvers to decrease modified LDL forms such as oxidized (oxLDL) and glycated (glyLDL) or glyco-oxidized LDL (gly-oxLDL) would represent a gigantic next step toward a revolution in the management of this common condition. In addition, it would be important to have instruments to decrease the uptake of modified LDL-C into macrophages by the SR-A and CD 36 scavenger receptors (SR) and to decrease inflammatory and oxidative stress and abnormal vascular immune responses. All of these approaches would reduce vascular damage beyond just treating LDL-C levels.25,26,27,28,29,30,31 There are at least 45 potential mechanisms that can be treated in the pathways involving dyslipidemia-induced vascular damage. We now know that lowering of serum hsCRP, an inflammatory marker and mediator, leads to fewer cardiovascular events independent of reductions in LDL-C cholesterol.30
Treatment
Overview
Many patients cannot tolerate or will not in principle use pharmacologic treatments such as statins, fibrates, bile-acid binders, ezetimibe, or PCSK9 inhibitors to treat dyslipidemia.5 Other patients with definitive indications for use of statins and other antilipid therapies prefer their use for many reasons such as cost, convenience, and proven efficacy. The most informed patients prefer to use an integrative approach to lipid management as clinical trials indicate an improved risk reduction in CHD and MI with combinations of nutraceuticals and drugs.
Drug-induced side effects (myopathy, myositis, rhabdomyolysis, abnormal liver function tests, neuropathy, memory loss, mental status changes, decreased focus and concentration, gastrointestinal disturbances, glucose intolerance or type 2 DM) are the largest reason why patients find lipid management notoriously disagreeable.32,33,34,35 With prolonged or high-dose usage of statin medications, patients may experience other clinical symptoms such as chronic fatigue, exercise-induced fatigue with myalgias and muscle weakness, reduced exercise tolerance, and loss of lean muscle mass. In addition, there may be reductions in both serum and tissue levels of coenzyme Q 10, carnitine, copper, zinc, creatine, vitamin E (tocopherols and tocotrienols), vitamin D, vitamin A, vitamin K2, selenium, selenoproteins, heme A, steroid, and sex hormone. Statins also may reduce the conversion of thyroxine (T4) to free tri-idothyronine (T3) by inhibiting the deiodinase enzyme, resulting in hypothyroidism.5,32,36,37,38,39,40,41,42,43 The newer PCSK9 inhibitors are free of most of these adverse effects because they are monoclonal antibodies and therefore they do not penetrate cells, are not metabolized by the liver, and are not perceived as xenobiotics by the body.44
New treatment approaches that combine weight loss, reductions in visceral and total body fat with increases in lean muscle mass, optimal aerobic and resistance exercise, and scientifically proven nutrition, use of nutritional supplements, and lipid-lowering drugs will improve serum lipids and reduce vascular inflammation, oxidative stress, abnormal vascular immune dysfunction, ED, and VSMD. In addition, both surrogate markers for vascular disease and rates of clinical end points such as CHD and MI are reduced in clinical trials.5 This chapter will review nutrition, nutritional supplements, and lipid-lowering drugs in the treatment of dyslipidemia and dyslipidemia-induced vascular disease. The reader is referred to an extensive body of literature on the role of exercise, weight loss, and other lifestyle treatments for dyslipidemia.
Nutrition
FRAMINGHAM HEART STUDY AND SEVEN COUNTRIES STUDY
Nutrition has long been recognized as an important modality for managing and preventing dyslipidemia and other risk factors for CVD, MI, and CHD.45 The Framingham Heart Study (FHS) and Seven Countries studies (SCS) found associations between increased LDL-C and TC levels with increased risk of CVD, and between elevated levels of HDL-C and decreased risk of CVD. An association between CVD and dietary fat consumption was also identified at that time, and a general link was established between Western diet, lipid levels, CHD, and CVD.46,47,48 The FHS initially included a cohort of 5209 healthy, mostly Caucasian residents of Framingham, Massachusetts, aged 30 to 60 years, and then added a second cohort of 5124 offspring in 1971. The last FHS cohort included 500 minorities.49 It should be noted that this is an epidemiologic, hypothesis-generating study with a small number of subjects of a single race. The ability to apply these conclusions to a broader population was to be verified later.
 Figure 22.2 A and B lipoproteins and atherosclerosis and atherosclerotic plaque formation. Proposed mechanisms of actions of nutraceuticals and statins in the dyslipidemia-induced atherosclerotic vascular disease pathway to the development of an atherosclerotic plaque. Diagrammed here are the various steps in the uptake of LDL-C, modification, macrophage ingestion with scavenger receptors, foam cell formation, oxidative stress, inflammation, autoimmune cytokines, and chemokine production. |
The SCS was a large prospective study that evaluated nutrition and lifestyle habits in 12,000 middle-aged men in Asia, Northern Europe, Southern Europe, and the United States. This study found a link between a high-fat diet and increased risk of CVD. The SCS has been criticized as to its validity because of selection bias and forced premises. It should also be noted that the high-fat diet consumed at that time was rich in TFA and long-chain SFA. Intake of omega-3 FA and MUFA was associated with a reduced risk of CHD. The SCS thus should not have bundled all dietary fats together in the link to increased risk of CVD.
PRITIKIN DIET
The Pritikin diet is a low-fat diet based primarily on vegetables, grains, and fruits with total fat supplying 10% of energy needs.50,51 Studies of this diet suggested that the dietary fat content reduced CVD and reduced LDL-C and TG and increased HDLC when coupled with a regular exercise program.52 It cannot be concluded that any one modality in this program was the primary reason for the CVD and lipid outcomes. A plant-based diet with exercise could have been the primary reason for the positive outcomes, more than the dietary fat reduction per se.
ORNISH DIET
The Ornish diet53 started from a randomized controlled trial (RCT) that had as its 1-year and 5-year end points LDL-C level, number of anginal episodes, and angiography-based regression of coronary stenosis.54,55,56 It was based on a combined intensive therapeutic approach of diet, exercise, and other lifestyle changes. The diet consisted of a low-fat, whole foods vegetarian diet with 10% of total energy as fat, drastic reduction (10 mg/d) in dietary cholesterol, increased intake of complex carbohydrates (fiber and plant-based nutrition), and minimal intake of simple sugars. Lifestyle modifications included moderate aerobic exercise, stress reduction, smoking cessation, and group psychosocial support. Compared with the control group, the experimental group had statistically significant reduction in LDL-C, a lower frequency of angina episodes, and regression of coronary artery stenosis at years 1 and 5. In contrast, the control group had minimal reduction in LDL-C, a significant increase in the frequency of angina episodes, and an increase in coronary artery stenosis. The dietary fat reduction here was primarily in long-chain SFA and TFA, which are now known to increase CHD risk. There was a concomitant increase in the intake of omega-3 FAs and MUFAs. The effects due to reduced consumption of these types of fats in combination with a plant-based diet, more fiber, and lower simple sugars are consistent with those of other studies using the same nutritional components, also showing a reduction in CHD rates. The comprehensive approach of nutrition, exercise, stress reduction, and smoking cessation, although certainly efficacious, does not allow one to pinpoint any single treatment as the primary reason for the clinical findings.
THERAPEUTIC LIFESTYLE CHANGES DIET
The National Heart, Lung, and Blood Institute (NHLBI) and the Adult Treatment Panel III of the National Cholesterol Education Program (ATP III) recommends the Therapeutic Lifestyle Changes (TLC) nutritional program with dietary SFA of <7% of total energy, dietary cholesterol of <200 mg/d, 10 to 25 g/d of viscous fiber, and 2 g/d of plant sterols/stanols.57,58 A randomized crossover study of 36 moderately hypercholesterolemic subjects treated over a period of 1 month compared the TLC diet (28% total fat, <7% SFA, 66 mg cholesterol/1000 kcal) with a Western diet (38% total fat, 15% SFA, 164 mg cholesterol/1000 kcal. Compared with the Western diet, the TLC diet significantly reduced plasma levels of both LDL-C (by 11%) and HDL-C (by 7%), with no significant effect on TG or the TC/HDL-C ratio.59 These net lipid changes are not impressive as the decrease in LDL was negated by the decrease in HDL. The lack of change in the TC/HDL ratio would predict no change in CHD risk over time. Moreover, in the 15-year Women’s Health Initiative, a multicenter randomized clinical trial of 48,835 postmenopausal women, a diet low in fat (20% of total calories), high in fruits and vegetables (five or more servings/d), and high in grains (six or more servings/d) did not show an effect on CVD rates or improvement in lipid profile. The type of fat reduction and the relatively low intake of fruits and vegetables could account for the negative CV outcomes.60 The addition of plant sterols in the TLC could also have biased the results in that study.
OMNIHEART TRIAL
The Optimal Macronutrient Intake for Heart Health trial (OmniHeart trial) investigated the effect of a Mediterranean-style diet on plasma lipids and blood pressure.49 In this randomized controlled intervention crossover study of generally healthy adults, three diets were compared for 6 weeks in each of the three groups (total 18 weeks): a carbohydrate-rich diet, a protein-rich diet, and a diet rich in MUFAs. The MUFA diet did not change LDL-C levels but increased HDL-C levels, the protein-rich diet decreased LDL-C and HDL-C levels, and all three diets reduced serum TG. After adjustment for potential confounders, an OMNIHEART score higher by 1 point was associated with systolic/diastolic BP differences of −1.0/−0.5 mm Hg (both P < .001). Findings were comparable for men and women, for nonhypertensive participants, and with adjustment for antihypertensive treatment. The trial could not assess the effects on CHD as it was too short and underpowered with only 164 subjects.
PORTFOLIO DIET
The Portfolio diet61,62,63,64,65,66 is a vegetarian version of the low-fat TLC diet, with the addition of soluble fiber, nuts, soy protein, and plant sterols. In a 1-month randomized control feeding trial, the Portfolio diet was compared with the TLC control diet.61 The LDL-C fell an average of 35.0% compared with 12.1% on the control diet. A follow-up study found that the Portfolio diet reduced LDL-C equal to a statin medication.64
In a subsequent study of hyperlipidemic adults who were followed for 1 year on the Portfolio diet, about 50% had reductions in LDL-C of >20%.62 Increasing the MUFA content increased the HDL-C levels without changing LDL-C.65 In the largest RCT of the Portfolio diet to date, LDL-C levels in those following this diet were significantly lower than in those following a low-saturated-fat diet.66 Once again, the addition of plant sterols with fiber and more plant-based nutrition likely resulted in improved lipid profiles over the basic nutritional suggestions of just low-fat dieting in the TLC diet.
In a subsequent study of hyperlipidemic adults who were followed for 1 year on the Portfolio diet, about 50% had reductions in LDL-C of >20%.62 Increasing the MUFA content increased the HDL-C levels without changing LDL-C.65 In the largest RCT of the Portfolio diet to date, LDL-C levels in those following this diet were significantly lower than in those following a low-saturated-fat diet.66 Once again, the addition of plant sterols with fiber and more plant-based nutrition likely resulted in improved lipid profiles over the basic nutritional suggestions of just low-fat dieting in the TLC diet.
MEDITERRANEAN DIETS
The Mediterranean-style diet is characterized by a high intake of vegetables, fruits, bread and other cereal grains, potatoes, legumes, nuts, and seeds. MUFA with extra-virgin olive oil (EVOO) and nuts are the primary fats consumed, which is typically 15% to 20% of total calories. Animal product intake, such as meat, poultry, fish, dairy, and eggs, is low to moderate, and wine consumption is regular but in moderation.67 Several clinical trials on the Mediterranean-style diet and CVD are discussed subsequently.
LYON DIET HEART STUDY
The Lyon Diet Heart Study was the first intervention trial to investigate the effect of a Mediterranean-style diet on CVD risk. This randomized single-blind secondary prevention trial was conducted in a single center in the Lyon region of France and included over 600 participants with prior MI.68,69,70 The primary outcome measurement (fatal or nonfatal MI) was significantly reduced by the intervention over the 4-year study period. CV outcomes including recurrent stable angina and restenosis of grafts were decreased by 47%, whereas the composite of MI, cardiovascular death, and major secondary events was decreased by 67%. These changes were independent of serum lipid changes, which were not significantly different between the groups. The design introduced changes to the usual Mediterranean diet consumed in southern Europe that the study is not generally considered an appropriate test of the efficacy of that diet on CVD risk. For example, the diet was 30.5% fat, with 12.5% as MUFA, much lower than the 15% to 20% MUFA content in the diet of southern Europe. Furthermore, the diet was enriched in ALA, an omega-3 polyunsaturated fat, rather than the usual MUFA oleic acid.
INDIAN HEART STUDY
The Indian Heart Study was a case-control study of 350 Indian subjects with ischemic heart disease on the effect of a Mediterranean-style diet enriched in ALA.71 The control group was advised on smoking cessation, stress management regular exercise, and reduction of dietary fat and alcohol. Compared with the control group at the 1-year follow-up, the treatment group had a 38% reduction in nonfatal MI and a 32% reduction in fatal MI. There was a significant and dose-dependent inverse association between vegetable intake and CHD risk. The inverse association was stronger for green leafy vegetables; in multivariate analysis, persons consuming a median of 3.5 servings/wk had a 67% lower relative risk (RR, 0.33; 95% confidence interval [CI], 0.17, 0.64; P for trend = 0.0001) than did those consuming 0.5 servings/wk. Controlling for other dietary covariates did not alter the association. Cereal intake was also associated with a lower risk. Use of mustard oil, which is rich in alpha-linolenic acid, was associated with a lower risk than was the use of sunflower oil (for use in cooking: RR, 0.49 [95% CI, 0.24-0.99]; for use in frying, RR, 0.29 [95% CI, 0.13-0.64]). Diets that are rich in vegetables and use of mustard oil could contribute to the lower risk of CHD among Indians.
There are numerous other diets that have been recommended for weight management and blood sugar or lipid control. These include the Atkins diet; South Beach diet; ketogenic diet; Paleo diet; vegetarian, vegan, or plant-based diet; the Esselstyn diet; and the fasting mimicking diet. All of these will be discussed in other chapters. Of all these diets, the fasting mimicking diet shows the best results for control of weight, glucose, lipids, stem cell production, and possibly slowing the aging process.
Nutrigenomics
The importance of nutrigenomic effects on serum lipids, DM, CHD, MI, CVD, ASCVD, hypertension, inflammation, oxidative stress, immune function, and cancer have all been demonstrated in numerous clinical trials such as the FUNGENUT study, the GEMINAL study, and the PREDIMED study.72,73,74,75,76,77,78,79 These are discussed in the following sections.
FUNGENUT Study
Diet changes can influence both phenotypic outcomes and gene expression.72 The Functional Genomics and Nutrition (FUNGENUT) Study of Finnish subjects with metabolic syndrome was conducted over 3 months, and participants were randomly assigned to either a low-glycemic-load rye-pasta diet to curtail postprandial insulin response or a high-glycemic-load oat-wheat-potato diet promoting a high postprandial insulin response. Gene expression was determined on samples of subcutaneous adipose tissue.72
In the low-glycemic-load rye-pasta group, the insulinogenic index improved and 71 genes were downregulated, including genes involved in insulin signaling and apoptosis. In the high-glycemic-load oat-wheat-potato diet group, 62 genes were upregulated, such as those promoting oxidative stress and inflammation.72
The GEMINAL Study
The Gene Expression Modulation by Intervention with Nutrition and Lifestyle (GEMINAL)73 study reported changes in gene expression in 30 men with low-risk prostate cancer after a 3-month intensive diet-and-lifestyle intervention. The intervention consisted of a low-fat, plant-based diet; moderate exercise; stress management; and psychosocial group support. Microarray analysis of gene expression in prostate
biopsies taken before and after the intervention detected 453 downregulated genes, many associated with tumorigenesis, as a result of the intensive diet-lifestyle intervention.
biopsies taken before and after the intervention detected 453 downregulated genes, many associated with tumorigenesis, as a result of the intensive diet-lifestyle intervention.
PREDIMED Study
In the PREDIMED study,74 three diets were evaluated for their effects on gene expression. The control diet was a low-fat TLC diet; the experimental diets were a Mediterranean-style diet enhanced with either EVOO or mixed nuts. The Mediterranean-style diets, particularly the EVOO, decreased expression of genes related to inflammation, foam cell formation, and thrombosis.
Another cohort of the PREDIMED study75 investigated these same three diets over a 3-year period to determine the effects on body weight parameters of a variant of the IL6 gene (IL6 −174G>C, rs1800795) that overproduces this proinflammatory cytokine and is associated with increased body weight, waist circumference, and serum lipid levels. The change in weight was numerically greatest in the EVOO group but was not statistically significant between groups. When the population was stratified by genotype (GG+GC versus CC), the CC group experienced greater weight loss irrespective of diet type. Interestingly, these individuals had greater adiposity at baseline but lost significantly more weight than those with one or two copies of the G allele (P = .002). In the CC group the nut diet actually led to weight gain.
Analyses of intermediate markers of cardiovascular risk demonstrated beneficial effects of the Mediterranean diet on blood pressure, lipid profiles, lipoprotein particles, DM, inflammation, oxidative stress, and carotid atherosclerosis, as well as on the expression of proatherogenic genes.76,77,78,79 Nutrigenomics studies also demonstrated favorable interactions of a Mediterranean diet with cyclooxygenase-2 (COX-2), interleukin-6 (IL-6), apolipoprotein A2 (APOA2), cholesteryl ester transfer protein plasma (CETP), transcription factor 7-like 2 (TCF7L2), beta adrenergic receptor gene (ADR B2), interleukin (IL7R), interferon (IFN gamma), monocyte chemotactic protein (MCP), and tumor necrosis factor (TNF) alpha gene polymorphisms.76,77,78,79
Nutritional Conclusions and Recommendations
Despite some apparent conflicts in these studies, owing to variations in amount and types of fats, simple sugars, complex carbohydrates, fiber, and the use of plant sterols, one can draw fairly solid conclusions from these nutritional interventions:
TFAs increase LDL-C and TG, reduce HDL-C, and increase CHD risk.
FAs that are C-12 and longer increase LDL-C and TG and may increase or not change HDL-C. They are associated with an increased risk of CHD. Shorter-chain FAs of C-10 and below instead lower LDL-C and TG, increase HDL-C, and are not associated with an increased risk for CHD.
Increased dietary intake of simple sugars increases LDL-C and TG and lowers HDL-C and is associated with an increased risk of CHD.
Omega-3 FAs and MUFAs lower LDL-C and TG, increase HDL-C, and reduce CHD risk. They also have effects that are independent of serum lipids that decrease CHD risk.
Specific Foods, Nutrients, and Dietary Supplements
Omega-3 Fatty Acids
Observational, epidemiologic, and controlled clinical trials of dietary omega-3 FAs have shown significant reductions in serum TG, VLDL, and LDL-P and variable changes in LDL-C, along with an increase in HDL-C, HDL particle size, and HDL-P, all of which are associated with major reductions in all CVD events.5,80,81,82,83,84,85,86,87 The Diet and Reinfarction Trial (DART) demonstrated a decrease in mortality of 29% in men post MI. In DART, 2033 men who had recovered from MI were allocated to receive advice on each of three dietary factors: a reduction in fat intake with an increased ratio of polyunsaturated to saturated fat, an increase in fatty fish intake, and an increase in cereal fiber intake. The advice on fat was not associated with any difference in mortality. The subjects advised to eat fatty fish had a 29% reduction in 2-year all-cause mortality. This effect, which was significant, was not altered by adjusting for potential confounding factors. Subjects given fiber advice had a slightly higher mortality (not significant). The 2-year incidence of reinfarction plus death from ischemic heart disease was not significantly affected by any of the dietary regimens. A modest intake of fatty fish (two or three portions per week) may reduce mortality in men who have recovered from MI.
The Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto Miocardico (GISSI) enrolled 11,324 patients surviving an MI (less than 3 months). The patients were randomly assigned supplements of n-3 PUFA (1 g daily, n = 2836), vitamin E (300 mg daily, n = 2830), both (n = 2830), or none (control, n = 2828) for 3.5 years. The primary combined efficacy end point was death, nonfatal MI, and stroke. Treatment with n-3 PUFA, but not vitamin E, significantly lowered the risk of the primary end point (relative risk decrease 10%). There was a decrease in total mortality of 20%. CV deaths decreased by 30%, and sudden death was reduced by 45%. The Kuopio Ischemic Heart Disease Risk Factor Study5,80,81 was a prospective population study of 871 men aged 42 to 60 years who had no clinical CHD at baseline examination. A total of 194 men had a fatal or nonfatal acute coronary event during follow-up. In a Cox proportional hazards’ model adjusting for other risk factors, men in the highest quintile of serum DHA in all FAs had a 44% reduced risk (P = .014) of acute coronary events compared with men in the lowest quintile. Men in the highest quintile who had a low hair content of mercury had a 67% reduced risk (P = .016) of acute coronary events compared with men
in the lowest quintile and with a high hair content of mercury. There was no association between EPA levels and the risk of acute coronary events. Fish oil-derived FAs reduce the risk of acute coronary events. However, a high mercury content in fish could attenuate this protective effect.5,80,81 The range of omega-3 FA was from 500 to 1000 mg/d in these studies and included both food and supplemental sources.
in the lowest quintile and with a high hair content of mercury. There was no association between EPA levels and the risk of acute coronary events. Fish oil-derived FAs reduce the risk of acute coronary events. However, a high mercury content in fish could attenuate this protective effect.5,80,81 The range of omega-3 FA was from 500 to 1000 mg/d in these studies and included both food and supplemental sources.
Omega-3 FAs reduce CHD progression, stabilize plaque, reduce coronary artery stent restenosis, and reduce graft restenosis.5,82 In the Japan EPA Lipid Intervention Study (JELIS), the addition of 1.8 g of EPA to a statin resulted in an additional 19% relative risk reduction (RRR) in major coronary events and nonfatal MI and a 20% decrease in CVA.5,83 A recent very large meta-analysis of 825,000 subjects80 included 18 RCTs and 16 prospective cohort studies examining the combination of EPA + DHA from foods or supplements and CHD, including MI, sudden cardiac death, coronary death, and angina.
In the RCTs, there was a nonstatistically significant reduction in CHD risk of 6% with EPA + DHA (summary relative risk elements = 0.94; 95% CI, 0.85-1.05).
However, subgroup analyses of data from these RCTs indicate a statistically significant CHD risk reduction with the combination of EPA + DHA (dose range of 340 mg/d to 5000 mg/d) among higher-risk populations with TG levels over 150 mg/dL (16% reduction in CHD) and/or LDL-C over 130 mg/dL (14% reduction in CHD). A meta-analysis of data from these 16 prospective cohort studies resulted in a statistically significant decrease in CHD of 18% for higher intakes of EPA + DHA from diet and supplement and risk of any CHD event.
Although the value is not statistically significant, a 6% reduced risk of any CHD event was observed among RCTs, a finding supported by a statistically significant 18% reduced risk of CHD among the prospective cohort studies. From a clinical perspective, these results indicate that EPA + DHA are associated with reducing CHD risk to a greater extent in populations with elevated TG levels or LDL-C, which affect a significant portion of the general adult population in the United States.80 In addition, a significant reduction in CHD rates in patients with known CHD was reported for a dietary intake over 1000 mg daily of combined DHA and EPA with a longer duration of treatment.
EPA and DHA in combination demonstrate a dose-related reduction in VLDL and TG of up to 50%, with a decrease in total TC, and ApoB, and a slight increase in LDL size and increase in HDL-C, HDL-P, and HDL size at the very high dose of 5 g/d. Lower doses, used by most, have less favorable effects on lipids.5,84,85,86,87 Despite a small increase in LDL-C in some subjects, the other lipid changes were beneficial and reduced the risk of CHD and MI. Patients with LDL-C over 100 mg/dL usually have reductions in total LDL-C, and those that are below 80 mg/dL have mild increases.86 The rate of entry of VLDL particles into the circulation is decreased by omega-3, and the lowering of APOCIII allows lipoprotein lipase to be more active. There was also a decrease in remnant chylomicrons and remnant lipoproteins.5,85 Omega-3 fats are also anti-inflammatory and antithrombotic and lower blood pressure, heart rate, and improve heart rate variability.5,80
Insulin resistance is improved and there are slight decreases or no significant changes in fasting glucose or hemoglobin A1c with long-term supplementation with omega-3 FA at doses up to 5000 mg/d.5,88 The combination of plant sterols and omega-3 FAs appears to be synergistic in improving lipids and inflammation.87
A recent meta-analysis of omega-3 FA and CVD has suggested no beneficial effect on CHD.89 This is at variance with the Mayo Clinic meta-analysis as well as the large body of published literature showing improved CHD risk with omega-3 FA. The more recent meta-analysis included only 10 trials involving 77,917 individuals compared with 34 trials and 825,000 subjects in the Mayo Clinic meta-analysis. Its limitations include:
Exclusion of data with arbitrary selection of studies: 500 individuals for at least 1 year (1-6.2 years) and no minimum dose of omega-3 required. Included both RCTs8 and open-label studies.2 Only 10 studies included with a total of 77,917 individuals.
Many studies used nontherapeutic, low doses of DHA and EPA. The EPA dose ranged from 226 to 800 mg/d and the DHA dose 0 to 1700 mg/d. Most studies used <1800 mg EPA/DHA in the high-risk CV population. Only three studies used >1800 mg EPA/DHA per day.
There was no monitoring of blood or tissue levels of omega-3 FAs, no compliance evaluations, and no omega-3 index data showing achievement of the minimal therapeutic level of 8%.
The studies with best results used the higher doses of DHA and EPA.
The larger studies with over 10,000 subjects and those consuming 1000 mg or more of omega-3 FA all had reductions in CV events (JELIS R and P, GISSI-P).
There were insufficient numbers of subjects in many studies to show any CV effect.
The quality of DHA/EPA may not have been good or it was not mentioned. Omega-3 FA was from the ester form in 9/10 trials.
CV morbidity and mortality was nominally lower in most of the studies, which suggests that benefits favor treatment.
In another recent Cochrane analysis of 79 RCTs with 112,059 subjects, the authors concluded that increasing consumption of EPA and DHA has little to no effect on mortality or CV health.90
RCTs that lasted at least 12 months were evaluated and compared supplementation and/or advice to increase LCn3 or ALA intake versus usual or lower intake. It included 79 RCTs with trials of 12 to 72 months’ duration and included adults at varying cardiovascular risk, mainly in high-income countries. Most studies assessed LCn3 supplementation with capsules, but some used LCn3- or ALA-rich or enriched foods or dietary advice compared with placebo or usual diet.
Meta-analysis and sensitivity analyses suggested little or no effect of increasing LCn3 on all-cause mortality
(RR, 0.98; 95% CI, 0.90 to 1.03; 92,653 participants; 8189 deaths in 39 trials), cardiovascular mortality (RR, 0.95; 95% CI, 0.87 to 1.03; 67,772 participants; 4544 CVD deaths in 25 RCTs), cardiovascular events (RR, 0.99; 95% CI, 0.94 to 1.04; 90,378 participants; 14,737 events in 38 trials), CHD mortality (RR, 0.93; 95% CI, 0.79 to 1.09; 73,491 participants; 1596 CHD deaths in 21 RCTs), stroke (RR, 1.06; 95% CI, 0.96 to 1.16; 89,358 participants; 1822 strokes in 28 trials), or arrhythmia (RR, 0.97; 95% CI, 0.90 to 1.05; 53,796 participants; 3788 events in 28 RCTs). There was a suggestion that LCn3 reduced CHD events (RR, 0.93; 95% CI, 0.88 to 0.97; 84,301 participants; 5469 events in 28 RCTs); however, this was not maintained in sensitivity analyses.
(RR, 0.98; 95% CI, 0.90 to 1.03; 92,653 participants; 8189 deaths in 39 trials), cardiovascular mortality (RR, 0.95; 95% CI, 0.87 to 1.03; 67,772 participants; 4544 CVD deaths in 25 RCTs), cardiovascular events (RR, 0.99; 95% CI, 0.94 to 1.04; 90,378 participants; 14,737 events in 38 trials), CHD mortality (RR, 0.93; 95% CI, 0.79 to 1.09; 73,491 participants; 1596 CHD deaths in 21 RCTs), stroke (RR, 1.06; 95% CI, 0.96 to 1.16; 89,358 participants; 1822 strokes in 28 trials), or arrhythmia (RR, 0.97; 95% CI, 0.90 to 1.05; 53,796 participants; 3788 events in 28 RCTs). There was a suggestion that LCn3 reduced CHD events (RR, 0.93; 95% CI, 0.88 to 0.97; 84,301 participants; 5469 events in 28 RCTs); however, this was not maintained in sensitivity analyses.
Increasing ALA intake does not impact all-cause mortality (RR, 1.01; 95% CI, 0.84 to 1.20; 19,327 participants; 459 deaths, five RCTs) and cardiovascular mortality (RR, 0.96; 95% CI, 0.74 to 1.25; 18,619 participants; 219 cardiovascular deaths, four RCTs), although it may slightly benefit CHD events (RR, 1.00; 95% CI, 0.80 to 1.22; 19,061 participants; 397 CHD events, four RCTs).
There was no evidence that increasing LCn3 or ALA altered serious adverse events, adiposity, or lipids, although LCn3 slightly reduced TG and increased HDL. The authors actually show a 5% to 7% reduction in CHD mortality with omega-3 FAs despite their negative conclusion. There are potential limitations and sources of variability that should be noted in all meta-analyses. The individual RCTs differed in terms of CHD prevalence at baseline, the EPA + DHA dosage provided, follow-up duration, and the methods of patient selection and randomization. The benefit of n-3 LCPUFA intake is likely to accrue over time, but RCTs of longer duration may suffer from poorer compliance with dietary supplementation. The variable use of terminology specific to CHD outcomes, or a lack of specificity required to discern CHD from broader CVD outcomes, is problematic. Many of the RCTs lacked statistical power to detect an effect because of relatively small sample sizes and/or few observed events due to the increased survival rate associated with current standards of care. Finally, most RCTs did not measure the baseline intake of EPA + DHA from the diet nor did they track EPA + DHA intake from sources other than that supplemented during the course of study, thus making it impossible to determine whether background dietary EPA + DHA intake affected the relationship between supplemental EPA + DHA and CHD.
Neither JAMA nor the Cochrane analysis has the validity of the Mayo Clinic meta-analysis, which included more appropriate types of studies, more than 825,000 subjects, better analysis, and less bias. Based on all published clinical trials, RCTs, cohort studies, and meta-analysis, these are the most valid conclusions regarding omega-3 FA dietary intake and CHD.
CHD is reduced by 16% in patients with TG over 150 mg/dL.
CHD is reduced by 14% in patients with LDL-C over 130 mg/dL.
DHA and EPA over 1000 mg/d significantly reduce CHD in both primary and secondary prevention settings.
A longer duration of treatment results in a greater reduction in CHD.
Secondary prevention trials with known CHD have shown more robust reductions of CHD event rates.
Flax
Flax seeds and flax lignan complexed with SDG (secoisolariciresinol diglucoside) have been shown in several meta-analyses to reduce TC and LDL-C by 5% to 15%, Lp(a) by 14%, and TG by up to 36%, with either no change or a slight reduction in HDL.5,91,92,93 These properties do not apply to flax seed oil. Flax seeds contain fiber and lignans that reduce the levels of 7 alpha hydroxylase and acyl CoA cholesterol transferase to decrease LDL-C, TG, and Lp(a).5,91,92,93 Flax seeds and ALA are anti-inflammatory, increase endothelial nitric oxide synthase (eNOS), improve ED, decrease vascular smooth muscle hypertrophy, reduce oxidative stress, and reduce the risk of CHD.5,91,92,93 The dose required for these effects is from 14 to 40 g of flax seed per day.5,91,92,93
Monounsaturated Fats
MUFAs such as those in olive oil, especially EVOO, and nuts reduce LDL-C by 5% to 10%, lower TG 10% to 15%, increase HDL 5%, improve HDL function, increase cholesterol efflux capacity (CEC), and decrease oxLDL. In addition, MUFAs reduce vascular inflammation and oxidation; decrease IL-23, IL-8, intracellular adhesion molecule, vascular cell adhesion molecule, and TNF alpha; improve ED; lower blood pressure; and decrease thrombosis. The net effect is to reduce the incidence of CHD by 30% (PREDIMED diet).5,74,75,94,95,96 In a study of 195 subjects,95 replacing SFAs with MUFAs or n-6 PUFAs did not affect the percentage change in flow-mediated dilatation (primary end point) or other measures of vascular reactivity, but the substitution of SFAs with MUFAs attenuated the increase in night systolic blood pressure (−4.9 mm Hg, P = .019) and reduced E-selectin (−7.8%, P = .012). Replacement of SFAs with MUFAs or n-6 PUFAs lowered fasting serum TC (−8.4% and −9.2%, respectively), LDL-C (−11.3% and −13.6%, respectively), and the TC/HDL ratio (−5.6% and −8.5%, respectively) (P ≤ .001). These changes in LDL-C equate to an estimated 17% to 20% reduction in CVD mortality. MUFAs are one of the most potent agents to reduce oxLDL.5 The equivalent of three to four tablespoons (30-40 g) per day of EVOO in MUFA content is recommended for the maximum effect in conjunction with omega-3 FAs. The best ratio of EVOO to combined DHA and EPA is about 5:1.5 The polyphenol content of EVOO is important for its overall lipid and CV effects. However, the caloric intake of this amount of MUFA must be balanced with the other beneficial effects.
Garlic
Numerous placebo-controlled clinical trials in humans indicate reductions in TC and LDL-C of about 9% to 12% with a standardized extract of allicin and ajoene5,97 at doses of 600
to 900 mg/d. However, many studies have been poorly controlled and used different types and doses of garlic, which have given inconsistent results.5,97 The best form of garlic is the CV formulation of aged garlic. Garlic reduces intestinal cholesterol absorption and inhibits enzymes involved in cholesterol synthesis.5,97 In addition, garlic lowers blood pressure, has fibrinolytic and antiplatelet activity, reduces oxLDL, and may decrease coronary artery calcification.5,97,98
to 900 mg/d. However, many studies have been poorly controlled and used different types and doses of garlic, which have given inconsistent results.5,97 The best form of garlic is the CV formulation of aged garlic. Garlic reduces intestinal cholesterol absorption and inhibits enzymes involved in cholesterol synthesis.5,97 In addition, garlic lowers blood pressure, has fibrinolytic and antiplatelet activity, reduces oxLDL, and may decrease coronary artery calcification.5,97,98
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