SEARCH

SEARCH BY CITATION

Abstract

  1. Top of page
  2. Abstract
  3. New Concepts and Perspective
  4. Nutraceutical Supplements and the Management of Dyslipidemia
  5. Combinations
  6. Summary and Conclusions
  7. References

J Clin Hypertens (Greenwich). 2012;14:121–132. ©2012 Wiley Periodicals, Inc.

The combination of a lipid-lowering diet and scientifically proven nutraceutical supplements has the ability to significantly reduce low-density lipoprotein (LDL) cholesterol, increase LDL particle size, decrease LDL particle number, lower trigylcerides and very LDL levels, and increase total and high-density lipoprotein 2b cholesterol. In addition, inflammation, oxidative stress, and immune responses are decreased. In several prospective clinical trials, coronary heart disease and cardiovascular disease have been reduced with many nutraceutical supplements. This nutritional and nutraceutical supplement treatment is a valid alternative for patients who are intolerant to statins, cannot take other drugs for the treatment of dyslipidemia, or prefer alternative treatments. This new approach to lipid management to decrease vascular disease utilizes a functional medicine approach with a broader treatment program that will address the multitude of steps involved in lipid-induced vascular damage.

Dyslipidemia is considered one of the top 5 risk factors for cardiovascular disease (CVD), along with hypertension, diabetes mellitus (DM), smoking, and obesity.1 The mechanisms by which certain lipids induce vascular damage are complex, but from a pathophysiologic and functional medicine viewpoint, these include inflammation, oxidative stress, and autoimmune dysfunction.2–4 These pathophysiologic mechanisms lead to endothelial dysfunction and vascular smooth muscle dysfunction. The vascular consequences are CVD, coronary heart disease (CHD), myocardial infarction (MI), and cerebrovascular accidents (CVA).4

New Concepts and Perspective

  1. Top of page
  2. Abstract
  3. New Concepts and Perspective
  4. Nutraceutical Supplements and the Management of Dyslipidemia
  5. Combinations
  6. Summary and Conclusions
  7. References

Contributing factors for dyslipidemia include genetics, poor nutrition, obesity (especially visceral obesity), some pharmacologic agents such as select β-blockers and diuretics, tobacco products, DM, and lack of exercise.5 For example, several genetic phenotypes, such as apolipoprotein (Apo) E, result in variable serum lipid responses to diet, as well as CHD and MI risk.6,7 In addition, high-density lipoprotein (HDL) proteomics such as paroxonase (PON) 1 and scavenger receptor (SR) B1 increase CVD,8 and Sortilin I allele variants on chromosome 1p13 increases LDL and CHD risk by 29%.9

Recent studies suggest, however, that dietary cholesterol intake does not significantly alter serum cholesterol levels or CHD and that saturated fats have a minimal influence on serum lipids and CHD risk, whereas monounsaturated and polyunsaturated fats have a favorable influence on serum lipids and CHD risk. Increased refined carbohydrate intake may be more important in changing serum lipids and lipid subfractions than saturated fats and cholesterol through the effects on insulin resistance, atherogenic LDL, LDL particle number, very LDL (VLDL), triglycerides (TGs), and total HDL and HDL subfractions of cholesterol and thus contribute more to CHD risk than saturated fats.5,10–16

The validity of the Diet Heart Hypothesis, which implies that dietary saturated fats, dietary cholesterol, and eggs increase the risk of CHD, has been questioned.11–13 Trans fatty acids have definite adverse lipid effects and increase CVD and CHD risk, but omega-3 fatty acids and monounsaturated fats improve serum lipids and reduce CVD risk.5,10,12,14–16 Trans fats suppress transforming growth factor β responsiveness, which increases the deposition of cholesterol into cellular plasma membranes in vascular tissue.15

Expanded lipid profiles that measure lipids, lipid subfractions, particle size and number, and Apo B are preferred to standard lipid profiles that measure only total cholesterol (TC), LDL, TGs, or HDL. The expanded lipid profiles such as lipoprotein particles (Spectracell Laboratories, Houston, TX), nuclear magnetic resonance (LipoScience, Raleigh, NC), Berkeley HeartLab (Alameda, CA), and vertical auto profile (Atherotec, Inc, Birmingham, AL), improve serum lipid analysis and CHD risk profiling and are more accurate in evaluating the serum lipid changes that occur with exercise, nutrition, weight loss or gain, other lifestyle changes, nutritional supplements, and drugs.17,18 Proper diagnosis, CHD risk assessment, and evaluation of nondrug or drug treatment is more accurate using the new expanded lipid profiles.17,18 New concepts in dysfunctional or inflammatory HDL19 and ability to evaluate it directly or indirectly measuring reverse cholesterol transport20 or myeloperoxidase21 will allow even better assessment of serum lipids, CHD risk, and treatment.

An understanding of the pathophysiologic steps of dyslipidemia-induced vascular damage is necessary to properly treat this disease in a logical and advanced manner (Figure 1). The ability to interrupt all of the various steps in this pathway will allow more specific functional and metabolic treatments to reduce vascular injury, improve vascular repair systems, and maintain or restore vascular health. Native LDL, especially large-type A LDL, is not usually atherogenic until modified. However, there may exist an alternate pinocytosis mechanim that allows macrophage ingestion of native LDL that for up to 30% of the foam cell formation in the subendothelium.22,23 For example, decreasing LDL modification, the atherogenic form of LDL cholesterol, through decreases in oxidized LDL (oxLDL), glycated LDL (glyLDL), glyco-oxidized LDL (gly-oxLDL), and acetylated LDL (acLDL), reducing the uptake of modified LDL into macrophages by the SRs CD36 and the inflammatory, oxidative stress, and autoimmune responses, will reduce vascular damage beyond just treating the LDL cholesterol level.24–29 There are at least 38 potential mechanisms that can be treated in the pathways that involve dyslipidemia-induced vascular damage and disease (Table I). Reductions in high-sensitivity C-reactive protein (hs-CRP), an inflammatory marker, reduce vascular events independent of reductions in LDL cholesterol through numerous mechanisms.30

image

Figure 1.  The various steps in the uptake of low-density lipoprotein (LDL) cholesterol, modification, macrophage ingestion with scavenger receptors, foam cell formation, oxidative stress, inflammation, autoimmune cytokines, and chemokine production. PAI-1 indicates plasminogen activator inhibitor-1; MCP-1, monocyte chemoattractant protein-1.

Download figure to PowerPoint

Table I.   Mechanisms for Treatment of Dyslipidemia-Induced Vascular Disease
Decrease endothelial permeability, gap junctions, and endothelial dysfunction and improve endothelial repair
Modify caveolae, caveolin-1, lipid rafts, membrane microdomains, unesterified cholesterol, and cholesterol crystals
Increase endothelial nitric oxide synthase and nitric oxide
Modify pattern recognition receptors (PRRs) activation and toll-like receptors
Decrease cholesterol crystals, low-density lipoprotein (LDL) phospholipids, oxidized LDL, apolipoprotein (Apo) B, and 7 ketosteroids that activate PRRs
Decrease LDL burden
Reduce cholesterol absorption
Increase cholesterol bile excretion
Decrease LDL particle number
Decrease Apo B
Decrease LDL modification
Inhibit LDL glycation
Increase LDL size
Modify LDL composition
Upregulate LDL receptor
Regulate sortilins and sortilin-related receptor with A-type repeats
Deactivate the lectin-like oxidized LDL receptor 1
Decrease modified LDL macrophage uptake by scavenger receptors
Decrease native LDL macrophage uptake by pinocytosis
Decrease LDL signaling
Decrease macrophage recruitment and migration
Alter macrophage phenotype
Modify signaling pathways
Increase reverse cholesterol transport
Increase high-density lipoprotein (HDL) and increase HDL size
Improve HDL function
Increase Apo A1
Increase paroxonase (PON) 1 and PON 2
Reduce inflammation
Reduce oxidative stress
Modulate immune dysfunction
Decrease very LDL and triglycerides
Lower lipoprotein(a)
Reduce foam cell and fatty streak formation
Reduce trapping of foam cells in the subendothelium
Stabilize plaque
Reduce LpPLA2
Reduce plaque burden, progression and increase regression

Many patients cannot or will not use pharmacologic treatments such as statins, fibrates, bile acid resin binders, or ezetimibe to treat dyslipidemia,5 because of side effects that include statin- or fibrate-induced muscle disease, abnormal liver function tests, neuropathy, memory loss, mental status changes, gastrointestinal disturbances, glucose intolerance, or DM.31–34 However, many patients have other clinical symptoms or laboratory abnormalities such as chronic fatigue, exercise-induced fatique, myalgias, muscle weakness, memory loss, loss of lean muscle mass–reduced exercise tolerence, reductions in coenzyme Q10, carnitine, vitamin E, vitamin D, omega-3 fatty acids, selenium, and free T3 levels (hypothyroidism) with prolonged usage or the administration of high-dose statins.5,31,35–42

New treatment approaches that combine weight loss, reduction in visceral and total body fat, increases in lean muscle mass, optimal aerobic and resistance exercise, scientifically proven nutrition, and use of nutraceutical supplements offer not only improvement in serum lipids but also reductions in inflammation, oxidative stress, immune dysfunction, endothelial, and vascular smooth muscle dysfunction. In addition, surrogate markers for vascular disease or clinical vascular target organ damage such as CHD have been shown to decrease in many clinical trials.5 This paper will review only nutraceutical supplements in the treatment of dyslipidemia (Table II). The reader is referred to an extensive body of literature on the role of nutrition, exercise, weight loss, and other lifestyle treatments for dyslipidemia.

Table II.   Nutritional Supplement Effects on the Various Mechanisms of Dyslipidemic-Induced Vascular Disease
Inhibition of LDL oxidation
 Niacin
 Green tea extract and green tea
 Pantethine
 Resevertrol
 Monounsaturated fats
 Curumin
 Pomegranate
 Garlic
 Sesame
 Gamma/delta tocotrienols
 Lycopene
 Polyphenols
 Oleic acid
 Glutathione
 Citrus bergamot
 Policosanol
Inhibition of low-density lipoprotein glycation
 Carnosine
 Histidine
 Myricetin
 Kaempferol
 Rutin
 Morin
 Pomegranate
 Organosulfur compounds
Lower low-density lipoprotein
 Niacin
 Red yeast rice
 Plant sterols
 Sesame
 Tocotrienols (gamma/delta)
 Pantethine
 Citrus bergamot
 Green tea extract and green tea
 Omega 3 fatty acids
 Flax seed
 Monounsaturated fats
 Garlic
 Resveratrol
 Curcumin
 Orange juice
 Soluble fiber
 Krill oil (?)
Convert dense low-density lipoprotein B to large low-density lipoprotein A
 Niacin
 Omega 3 fatty acids
 Plant sterols
Reduce intestinal cholesterol absorption
 Plant sterols
 Soy
 Green tea extract and green tea
 Flax seeds
 Sesame
 Garlic
 Fiber
HMG CoA reductase inhibition
 Red yeast rice
 Pantethine
 Gamma/tocotrienols
 Sesame
 Green tea extract and green tea
 Omega 3 fatty acids
 Citrus bergamot
 Garlic
 Curcumin
 Gamma-linolenic acid
 Plant sterols
Lower lipoprotein(a)
 Niacin
 N acetyl cysteine
 Gamma delta tocotrienols
 Omega 3 fatty acids
 Flax seed
 Coenzyme Q10
 Vitamin C
 l Carnitine
 l-Lysine
 l-Arginine
Lower triglycerides
 Niacin
 Red yeast rice
 Omega 3 fatty acids
 Pantethine
 Citrus bergamot
 Flax seed
 Monounsaturated fats
 Resveratrol
 Orange juice
 Krill oil (?)
Increase total high-density lipoprotein (HDL) and HDL 2b levels and convert HDL 3 to HDL 2 and 2b
 Niacin
 Omega 3 fatty acids
 Pantethine
 Red yeast rice
 Monounsaturated fats
 Resveratrol
 Curcumin
 Pomegranate
 Orange juice
 Citrus bergamot
 Krill oil (?)
Alter scavenger receptor nicotinamide adenine dinucleotide phosphate-oxidase and oxidized low-density lipoprotein uptake into macrophages
 Resveratrol
 N acetyl cysteine
Increase reverse cholesterol transport
 Lycopene
 Plant sterols
 Glutathione
Decrease low-density lipoprotein particle number
 Niacin
 Omega 3 fatty acids
Reduce inflammation
 Niacin
 Omega 3 fatty acids
 Flax seed
 Monounsaturated fats
 Plant sterols
 Guggulipids
 Resveratrol
 Glutathione
Lower apolipoprotein B lipoprotein
 Niacin
 Omega 3 fatty acids
 Plant sterols
 Green tea extract and green tea
Increase apolipoprotein A1 lipoprotein
 Niacin
Decrease low-density lipoprotein particle number
 Niacin
 Omega 3 fatty acids
Upregulate the low-density lipoprotein receptor
 Green tea extract and green tea
 Sesame
 Tocotrienols
 Curcumin
 Policosanol
 Plant sterols
Increase paroxonase 1 and paroxonase 2
 Green tea extract and green tea
 Ouercetin
 Pomegranate
 Resveratrol
 Glutathione
Increase bile acid excretion
 Resveratrol
 Citrus bergamot
 Fiber
 Probiotics
 Plant sterols
 Sesame
Nutraceutical supplemet recommend doses for the treatment of dyslipidemia
 SupplementDaily dose
  Niacin: vitamin B 3500–4000 mg in divided doses
  Phytosterols2.15 g
 Soy (fermented)30–50 g
 Green tea extract and green tea500–700 mg
 Omega 3 fatty acids3000–5000 mg
 Flax seed40 g
 Monounsaturated fats20–40 g
 Sesame40 g
 Gamma/delta tocotrienols200 mg
 Pantethine900 mg in divided doses
 Resveratrol (trans form)250 mg
 N acetyl cysteine2000 mg in divided doses
 Curcumin2000 mg in divided doses
 Pomegranate juice8 ounces
 Citrus bergamot1000 mg
 Vitamin C500 mg

Nutraceutical Supplements and the Management of Dyslipidemia

  1. Top of page
  2. Abstract
  3. New Concepts and Perspective
  4. Nutraceutical Supplements and the Management of Dyslipidemia
  5. Combinations
  6. Summary and Conclusions
  7. References

Nutraceutical supplement management of dyslipidemia has been infrequently reviewed.5,43 New important scientific information and clinical studies are required to understand the present role of these natural agents in the management of dyslipidemia.5,43 These studies include clinical trials that show excellent reductions in both serum lipids and CHD (niacin, omega-3 fatty acids, red yeast rice, fiber, and alpha linolenic acid [ALA]), and smaller studies with reductions in surrogate vascular markers with numerous other nutraceutical supplements (carotid intima-media thickness [IMT] and obstruction, plaque progression, coronary artery calcium score by electron beam tomography [EBT], generalized atherosclerosis, and endothelial function).5,43–45 The proposed mechanisms of action of some of the nutraceutical supplements on the mammalian cholesterol pathway are shown in Figure 2.

image

Figure 2.  Proposed mechanisms of actions of nutraceuticals and statins in the cholesterol pathway.

Download figure to PowerPoint

Niacin (Vitamin B3)

Niacin has a dose-related effect (1–4 g per day) in reducing TC, LDL, Apo B, LDL particle number, TGs, VLDL, and increasing LDL size from small type B to large type A and high-density lipoprotein (HDL), especially the protective and larger HDL 2b particle and Apo A1.5

These changes vary from about 10% to 30% for each lipid level as noted above.5,46,47 Niacin inhibits LDL oxidation, increases TG lipolysis in adipose tissue, increases Apo B degradation, reduces the fractional catabolic rate of HDL-Apo A1, inhibits platelet function, induces fibrinolysis, decreases cytokines and cell adhesion molecules, lowers lipoprotein(a), increases adiponectin, and is a potent antioxidant.5,46,47 Randomized controlled clinical trials such as the Coronary Drug Project, the HDL-Atherosclerosis Treatment Study (HATS), the Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol (ARBITER 2), the Oxford Niaspan Study, the Familial Atherosclerosis Treatment Study (FATS), Cholesterol-Lowering Atherosclerosis Study (CLAS) I and CLAS II, and Armed Forces Research Study (AFRS) have shown reductions in coronary events, coronary atheroma (plaque), and carotid IMT.5,46–51 The recent negative findings in the Atherothrombosis Intervention in Metabolic Syndrome With Low HDL-C/High Triglyceride and Impact on Global Health Outcomes study52 do not detract from the positive results in previous trials, as this study was not powered to statistically determine CVD end points. The niacin dose should be gradually increased, administered at meal time, pretreated with 81-mg aspirin, and taken with apple pectin to reduce flushing.5 The effective dose range is from 500 mg to 4000 mg per day. Only vitamin B3 niacin is effective in dyslipidemia. The non-flush niacin (inositol hexanicotinate-IHN) does not improve lipid profiles and is not recommended.5 The side effects of niacin include hyperglycemia, hyperuricemia, gout, hepatitis, flushing, rash, pruritus, hyperpigmentation, hyperhomocysteinemia, gastritis, ulcers, bruising, tachycardia, and palpitations.5,46,47 If niacin is taken on a regular basis without missing doses, the flushing is minimized.

Policosanol

Policosanol is a sugar cane extract of 8 aliphatic alcohols that has undergone extensive clinical studies with variable results.5 Most of the earlier studies that showed positive results were performed in Cuba with questionable validity.5,43,53,54 The more recent double-blind, placebo-controlled clinical trials have not shown any significant improvement in any measured lipids including TC, LDL, TG, or HDL. Policosanol is not recommended at this time for the treatment of any form of dyslipidemia.5,43,53,54

Red Yeast Rice

Red yeast rice (RYR) (Monascus purpureus) is a fermented product of rice that contains monocolins that inhibit cholesterol synthesis via HMG-CoA reductase and thus has “statin-like” effects.5,43,53,54 RYR also contains sterols, isoflavones, and monounsaturated fatty acids. At 2400 mg per day, LDL is reduced 22% (P<.001) and TG decreases 12%, with little change in HDL.5,43,55 In a recent placebo-controlled Chinese study of 5000 patients over 4.5 years, an extract of RYR reduced LDL by 17.6% (P<.001) and increased HDL by 4.2% (P<.001).56 Cardiovascular mortality fell by 30% (P<.005) and total mortality fell by 33% (P<.0003) in the treated patients. The overall primary end point for MI and death was reduced by 45% (P<.001). A highly purified and certified RYR must be used to avoid potential renal damage induced by a mycotoxin, citrinin.5,43,55 The recommended dose is 2400 mg to 4800 mg of a standardized RYR. No adverse clinical effects have been reported with long-term use. Although reductions in coenzyme Q10 may occur in predisposed patients and those taking prolonged high-dose RYR due to its weaker “statin-like” effect. RYR is an excellent alternative to patients with statin-induced myopathy.5,43,55,56

Plant Sterols (Phytosterols)

The plant sterols are naturally occurring sterols of plant origin that include B-sitosterol (the most abundant), campesterol and stigmasterol (4-desmethyl sterols of the cholestane series), and the stanols, which are saturated.5,43,57–59 The plant sterols are much better absorbed than the plant stanols. The daily intake of plant sterols in the United States is about 150 mg to 400 mg per day mostly from soybean oil, various nuts, and tall pine tree oil.42 These have a dose-dependent reduction in serum lipids.58 TC decreases by 8%, LDL decreases by 10% (range 6–15%) with no change in TGs or HDL on doses of 2 g to 3 g per day in divided doses with meals.5,42,57,58 A recent meta-analysis of 84 trials showed that an average intake of 2.15 g per day reduced LDL by 8.8% with no improvement with higher doses.58

The mechanism of action is primarily to decrease the incorporation of dietary and biliary cholesterol into micelles due to lowered micellar solubility of cholesterol, which reduces cholesterol absorption and increases bile acid secretion. In addition, there is an interaction with enterocyte ATP-binding cassette transport proteins (ABCG8 and ABCG 5) that directs cholesterol back into the intestinal lumen.5,43,57 The only difference between cholesterol and sitosterol consists of an additional ethyl group at position C-24 in sitosterol, which is responsible for its poor absorption. The plant sterols have a higher affinity than cholesterol for the micelles. Patients who have the rare homozygote mutations of the ATP-binding cassette are hyperabsorbers of sitosterol (absorb 15%–60% instead of the normal 5%) and will develop premature atherosclerosis.43 This is a rare autosomal recessive disorder termed sitosterolemia. The plant sterols are also anti-inflammatory and decrease the levels of pro-inflammatory cytokines such as hs-CRP, interleukin (IL) 6, IL-1b, tumor necrosis factor α, phospholipase 2, and fibrinogen, but these effects vary among the various phytosterols.59,60 Other potential mechanisms include modulation of signaling pathways, activation of cellular stress responses, growth arrest, reduction of Apo B 48 secretion from intestinal and hepatic cells, reduction of cholesterol synthesis with suppression of HMG-CoA reductase and CYP7A1, interference with sterol regulatory element-binding proteins (SREBPs), and promotion of reverse cholesterol transport via ABCA1 and ABCG1.60 The biological activity of phytosterols is both cell-type and sterol specific.60

The plant sterols can interfere with absorption of lipid-soluble compounds such as fat-soluble vitamins and carotenoids including vitamin D, E, K, and alpha carotene.5,43 Some studies have shown reduction in atherosclerosis progression, reduced carotid IMT, and decreased plaque progression, but the results have been conflicting.5,43 There are no studies on CHD or other CVD outcomes. The recommended dose is about 2 g to 2.5 g per day (average 2.15 g per day).

Soy

Numerous studies have shown mild improvements in serum lipids with soy at doses of about 30 g to 50 g per day.5,43,61,62 TC decreased by 2% to 9.3%, LDL by 4% to 12.9%, and TGs by up to 10.5% and HDL increased by up to 2.4%. However, the studies are conflicting due to differences in the type and dose of soy used in the studies, as well as nonstandardized methodology.5,43,61,62 Soy decreases the micellar content and absorption of lipids through a combination of fiber, isoflavones (genistin, glycitin, diadzin), and phytoestrogens.5,43,61,62 The most reduction is seen with soy-enriched isoflavones with soy protein. Fermented soy is preferred.

Green Tea Extract and Green Tea

Catechins, especially green tea extract and green tea (EGCG), may improve the lipid profile by interfering with micellar solubilization of cholesterol in the GI tract and reduce absorption.5 In addition, EGCG reduces the fatty acid gene expression, inhibits HMG-CoA reductase, increases mitochondrial energy expenditure, reduces oxLDL, increases PON 1, upregulates the LDL receptor, decreases Apo B lipoprotein secretion from cells, mimics the action of insulin, improves endothelial dysfunction, and decreases body fat.5,63–65

A meta-analysis of human studies of 14 trials show that EGCG at 224 mg to 674 mg per day or 60 oz of green tea per day reduced TC by 7.2 mg/dL and LDL by 2.19 mg/dL (P<.001 for both). There was no significant changes in HDL or TG levels.66 The recommended dose is a standardized EGCG extract of 500 mg to 700 mg per day.

Omega-3 Fatty Acids

Observational, epidemiologic, and controlled clinical trials have shown significant reductions in serum TGs, VLDL, and LDL particle number and increased LDL and HDL particle size, as well as major reductions in all CVD events.5,67–74 The Diet and Reinfarction Trial (DART) demonstrated a decrease in mortality of 29% in men post-MI, and the Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto (GISSI) prevention trial found a decrease in total mortality of 20%, CV deaths of 30%, and sudden death of 45%. The Kuppio Heart Study demonstrated a 44% reduction in fatal and nonfatal CHD in patients in the highest quintile of omega 3 intake compared with the lowest quintile.5,67,68 Omega-3 fatty acids reduce CHD progression, coronary artery stent restenosis, and CABG occlusion and stabilize plaque.5,69 In the Japan EPA Lipid Intervention Study (JELIS), the addition of 1.8 g of omega-3 fatty acids to a statin resulted in an additional 19% relative risk reduction in major coronary events and nonfatal MI and a 20% decrease in cerebrovascular accidents.5,70

A dose-related reduction is seen of up to 50% in VLDL and up to 50% in TGs; little to no change or decrease in total TC, LDL, and Apo B; and no change to a slight increase in HDL.5,71–74 However, the number of LDL particles decreases and LDL particle size increases from small type B to large type A (increase of 0.25 nm). The antiatherogenic HDL 2b also increases by up to 29%. The rate of entry of VLDL particles into the circulation is decreased and Apo CIII is reduced, which allows lipoprotein lipase to be more active. There is a decrease in remnant chylomicrons and remnant lipoproteins.5,72 Patients with LDL >100 mg Hg usually have reductions in total LDL and those with LDL <80 mg Hg have mild increases.73 However, in both cases, the LDL particle number decreases, the dense LDL B increases in size to the less atherogenic LDL A particle, and Apo B levels decrease. There is a net decrease in the concentration of cholesterol carried by all atherogenic particles and decreases in non-HDL cholesterol. Omega-3 fatty acids are anti-inflammatory and anti-thrombotic, lower blood pressure and heart rate, and improve heart rate variability.5,67 There is a decrease in fatty acid synthesis and an increase in fatty acid oxidation with consistent weight loss.5

Insulin resistance is improved and there are no significant changes in fasting glucose or hemoglobin A1c with long-term treatment.75 Doses of 3 g per day of combined eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) at a 3:2 ratio (with gamma-linolenic acid at 50% of the total EPA and DHA content and 700 mg of gamma, delta, and alpha tocopherol at 80% gamma/delta and 20% alpha tocopherol per 3 g of DHA and EPA) are recommended.5 DHA and EPA may have variable but favorable effects on the various lipid levels.5,71,72,75 The combination of plant sterols and omega-3 fatty acids are synergistic in improving lipids and inflammation.74

Flax

Flax seeds and flax lignan complex with secoisolariciresinol diglucoside and increased intake of ALA from other sources such as walnuts have been shown in several meta-analyses to reduce TC and LDL by 5% to 15%, lipoprotein(a) by 14%, and TG by up to 36%, with either no change or a slight reduction in HDL.5,76–78 These effects do not apply to flax seed oil. In the Seven Countries Study, CHD was reduced with increased consumption of ALA, and in the Lyon Diet Trial at 4 years, intake of flax reduced CHD and total deaths by 50% to 70%.5 Flax seeds contain fiber and lignans and reduce the levels of 7 alpha hydrolyase and acyl CoA cholesterol transferase.5,76–78 Flax seeds and ALA are anti-inflammatory, increase endothelial nitric oxide synthase, improve endothelial dysfunction, contain phytoestrogens and decrease vascular smooth muscle hypertrophy, reduce oxidative stress, and retard development of atherosclerosis.5,76–78 The dose required for these effects ranges from 14 g to 40 g of flax seed per day.5,76–78

Monounsaturated Fats

Monounsaturated fats (MUFAs) such as olives, olive oil, and nuts reduce LDL by 5% to 10%, lower TGs by 10% to 15%, increase HDL by 5%, decrease oxLDL, reduce oxidation and inflammation, improve erectile dysfunction, lower blood pressure, decrease thrombosis, and reduce the incidence of CHD (Mediterranean diet).5,79–82 MUFAs are one of the most potent agents to reduce oxLDL. The equivalent of 3 to 4 tablespoons (30–40 g) per day of extra virgin olive oil found in MUFAs is recommended for the maximum effect in conjunction with omega-3 fatty acids. However, the caloric intake of this amount of MUFA must be balanced with the other beneficial effects.

Sesame

Sesame at 40 g per day reduces LDL by 9% through inhibition of intestinal absorption, increasing biliary secretion, decreasing HMG-CoA reductase activity, and upregulating the LDL receptor gene, 7 alpha hydroxylase gene expression, and the SREBP 2 genes.83,84 A randomized placebo-controlled crossover study of 26 postmenopausal women who consumed 50 g of sesame powder daily for 5 weeks had a 5% decrease in TC and a 10% decrease in LDL-C.79

Tocotrienols

Tocotrienols are a family of unsaturated forms of vitamin E termed alpha, beta, gamma, and delta.5 The gamma and delta tocotrienols lower TC by up to 17%, LDL by 24%, Apo B by 15%, and lipoprotein(a) by 17%, with minimal changes in HDL or Apo A1 in 50% of patients at doses of 200 mg per day given at night with food.5,85–87 The gamma/delta from of tocotrienols inhibits cholesterol synthesis by suppression of HMG-CoA reductase activity by two post-transcriptional actions.5,85–87 These include increased controlled degradation of the reductase protein and decreased efficiency of translation of HMG-CoA reductase mRNA. These effects are mediated by sterol binding of the reductase enzyme to the endoplasmic reticulum membrane proteins call INSIGS.86 The tocotrienols have natural farnesylated analogues of tocopherols, which give them their effects on HMG-CoA reductase.86 In addition, the LDL receptor is augmented and they exhibit anti-oxidant activity. The tocotrienol dose is important as increased dosing will induce its own metabolism and reduce effectiveness, whereas lower doses are not as effective.5 Also, concomitant intake (<12 hour) of alpha tocopherol reduces tocotrienol absorption. Increased intake of alpha tocopherol >20% of total tocopherols may interfere with the lipid-lowering effect.5,85

Tocotrienols are metabolized by successive beta oxidation then catalyzed by the CYP P450 enzymes 3A4 and CYP 4F2.5 The combination of a statin with gamma/delta tocotrienols futher reduces LDL cholesterol by 10%.85 The tocotrienols block the adaptive response of upregulation of HMG-CoA reductase secondary to competitive inhibition by the statins.5,85 Carotid artery stenosis regression has been reported in about 30% of patients given tocotrienols over 18 months. They also slow progression of generalized atherosclerosis.5,87 The recommended dose is 200 mg of gamma delta tocotrienol at night with food.

Pantethine

Pantethine is the disulfide derivative of pantothenic acid and is metabolized to cystamine-SH, which is the active form in treating dyslipidemia.5,88–92 More than 28 clinical trials have shown consistent and significant improvement in serum lipids. TC is decreased by 15%, LDL by 20%, Apo B by 27.6%, and TG by 36.5% over 4 to 9 months. HDL and Apo A1 are increased by 8%.5,88–92 The effects on lipids are slow, with peak effects at 4 months, but may take up to 6 to 9 months.5,88–92 In addition, pantethine reduces lipid peroxidation of LDL, lipid deposition, intimal thickening, and fatty streak formation in the aorta and coronary arteries.5,88–92 Pantethine inhibits cholesterol synthesis and acclerates fatty acid metabolism in the mitochondria by inhibiting hepatic acetyl-CoA carboxylase; increases CoA in the cytoplasm, which stimulates the oxidation of acetate at the expense of fatty acid and cholesterol synthesis; and increases Krebs cycle activity.5,88–92 In addition, cholesterol esterase activity increases and HMG-CoA reductase activity decreases.5,88–92 There is 50% inhibition of fatty acid synthesis and 80% inhibition of cholesterol synthesis.5 The recommended effective dose is 300 mg 3 times per day or 450 mg twice per day with or without food.5,88–92

Guggulipids

Guggulipids (Commiphora mukul) are resins from the mukul myrrh tree that contain active lipid-lowering compounds called guggulsterones.5,93–95 Guggulipids have been shown to increase hepatic LDL receptors and bile acid secretion and decrease cholesterol synthesis in animal experiments.5,89 However, controlled human clinical trials have not shown these agents to be effective in improving serum lipids.93–95 One study of 103 patients taking 50 mg to 75 mg of guggulsterones per day for 8 weeks actually had a 5% increase in LDL; no change in TC, TG, or HDL; and insignificant reductions in lipoprotein(a) and hs-CRP.93 Guggulipids are not recommended at this time.

Garlic

Numerous placebo-controlled clinical trials in humans have shown reductions in TC and LDL of about 9% to 12% at doses of 600 to 900 mg per day of a standardized extract of allicin and ajoene.5,96 However, many studies have been poorly controlled and use variable types and doses of garlic, which has provided inconsistent results.5,96 Garlic reduces intestinal cholesterol absorption, inhibits enzymes involved in cholesterol synthesis, and deactivates HMG-COA reductase.5,96 In addition, garlic lowers blood pressure, has fibrinolytic activity, antiplatelet activity, reduces oxLDL, and decreases coronary artery calcification by electron beam tomography.5,45,96

Resveratrol

Resveratrol reduces oxLDL; inhibits acyl-CoA:cholesterol acyltransferase transferase activity and cholesterol ester formation; increases bile acid excretion, reduces TC, TG, and LDL; increases PON 1 activity and HDL; inhibits nicotinamide adenine dinucleotide phosphate-oxidase in macrophages; and blocks the uptake of modified LDL by CD36 SRs.28N acetyl cysteine (NAC) has this same effect on CD 36 DR and should be used in conjunction with resveratrol.28 The dose of trans-resveratrol is 250 mg per day and NAC is 1000 mg twice per day.

Curcumin

Curcumin is a phenolic compound in tumeric and curry.5,97 It induces changes in the expression of genes involved in cholesterol synthesis such as the LDL receptor mRNA, HMG-CoA reductase, SREBP, cholesterol 7 alpha hydrolyze, peroxisome proliferator-activated receptors, and liver X receptor.5,97 In one human study of 10 patients who consumed 500 mg per day of curcumin, HDL increased by 29% and TC fell by 12%.5,97 This needs confirmation in larger randomized clinical trials.

Pomegranate

Pomegranate increases PON 1 binding to HDL and increases PON 2 in macrophages. It is a potent antioxidant, increases total antioxidant status, lowers oxLDL, decreases antibodies to oxLDL, inhibits platelet function, reduces glycosylated LDL, decreases macrophage LDL uptake, reduces lipid deposition in the arterial wall, decreases progression of carotid artery IMT, and lowers blood pressure, especially in patients with high oxidative stress, known carotid artery plaque, and the increased abnormalities in TG and HDL levels.98–103 Consuming about 8 oz of pomegranate juice per day is recommended.

Orange Juice

In one human study, 750 mL of concentrated orange juice per day over 2 months decreased LDL by 11%, with reductions in Apo B and TGs and increases in HDL by 21%.104 The effects are due to polymethoxylated flavones, hesperitin, naringin, pectin, and essential oils.104 Additional studies are needed to verify these data.

Citrus Bergamot

Citrus bergamot has been evaluated in several clinical prospective trials in humans. In doses of 1000 mg per day, this compound lowers LDL up to 36% and TG by 39%; increases HDL by 40% by inhibiting HMG-CoA reductase; increases cholesterol and bile acid excretion; and reduces reactive oxygen species and oxLDL.105,106 The active ingredients include naringin, neroeriocitrin, neohesperidin, poncerin, rutin, neodesmin, rhoifolin, melitidine, and brutelidine.105,106

Vitamin C

Vitamin C supplementation lowers serum LDL cholesterol and TGs.107 A meta-analysis of 13 randomized controlled trials in patients given at least 500 mg of vitamin C daily for 3 to 24 weeks found a reduction in LDL cholesterol of 7.9 mg/dL (P<.0001) and TG of 20.1 mg/dL (P<.003); HDL did not change. The reductions in LDL and TG were greatest in patients with the highest initial lipid levels and the lowest serum vitamin C levels.108

Lycopene

Lycopene has been shown in tissue culture to inhibit HMG-CoA reductase, induce Rho inactivation, increase peroxisome proliferator–activated receptor γ and liver X receptor activities, and reverse cholesterol transport and efflux with ABCA1 and Caveolin 1 expression.109

Disclosures:  Dr Houston did clinical research in the Hypertension Institute on a proprietary product mentioned (but not named) in this paper that is manufactured by Biotics Research Labs in Rosenberg, Texas.

Combinations

  1. Top of page
  2. Abstract
  3. New Concepts and Perspective
  4. Nutraceutical Supplements and the Management of Dyslipidemia
  5. Combinations
  6. Summary and Conclusions
  7. References

A recent prospective open-label human clinical trial of 30 patients for 2 months showed significant improvement in serum lipids using a proprietary product with a combination of pantethine, plant sterols, EGCG, gamma/delta tocotrienols, and phytolens.110 TC fell by 14%, LDL decreased by 14%, VLDL dropped by 20%, and small dense LDL particles fell by 25% (type III and IV).110 In another study using the same proprietary product with RYR 2400 mg to 4800 mg per day and niacin 500 mg per day, TC fell by 34%, LDL decreased by 34%, LDL particle number fell by 35%, VLDL dropped by 27%, and HDL increased by 10% (verbal communication, Houston MC. Unpublished data, 2011). Studies indicate a relative risk reduction of CVD mortality with omega-3 fatty acids of 0.68, with resins of 0.70, and with statins of 0.78.111 Combining statins with omega-3 fatty acids further decreases CHD by 19%.70 The combination of gamma/delta tocotrienols with a statin reduces LDL cholesterol an additional 10%.85 Plant sterols with omega-3 fatty acids have synergistic lipid-lowering and anti-inflammatory effects.74 Future studies are needed to evaluate various other combinations on serum lipids, surrogate vascular end points, and CHD and CVD morbidity and mortality.

Summary and Conclusions

  1. Top of page
  2. Abstract
  3. New Concepts and Perspective
  4. Nutraceutical Supplements and the Management of Dyslipidemia
  5. Combinations
  6. Summary and Conclusions
  7. References

The combination of a lipid-lowering diet and selected scientifically proven nutraceutical supplements has the ability to reduce LDL cholesterol by up to 50%, increase LDL particle size, decrease LDL particle number, lower TG and VLDL, and increase total and type 2b HDL. In addition, inflammation, oxidative stress, immune responses, vascular target organ damage, atherosclerosis, and CVD are reduced. In several prospective clinical trials, CHD and CVD have been shown to be reduced with many of the nutraceutical supplements discussed in this paper. This nutritional and nutraceutical supplement treatment is a valid alternative for patients who are statin intolerant, cannot take other drugs for the treatment of dyslipidemia, or in those who prefer alternative treatments. This new approach to lipid management to decrease vascular disease uses a more functional medicine approach with a broader treatment program that addresses the multitude of steps involved in lipid-induced vascular damage.

References

  1. Top of page
  2. Abstract
  3. New Concepts and Perspective
  4. Nutraceutical Supplements and the Management of Dyslipidemia
  5. Combinations
  6. Summary and Conclusions
  7. References
  • 1
    Kannel WB, Castelli WD, Gordon T, et al. Serum cholesterol, lipoproteins and risk of coronary artery disease. The Framingham Study. Ann Intern Med. 1971;74:112.
  • 2
    Houston MC. Nutrition and nutraceutical supplements in the treatment of hypertension. Expert Rev Cardiovasc Ther. 2010;8:821833.
  • 3
    Tian N, Penman AD, Mawson AR, et al. Association between circulating specific leukocyte types and blood pressure: the atherosclerosis risk in communities (ARIC) study. J Am Soc Hypertens. 2010;4:272283.
  • 4
    Ungvari Z, Kaley G, de Cabo R, et al. Mechanisms of vascular aging: new perspectives. J Gerontol A Biol Sci Med Sci. 2010;65:10281041.
  • 5
    Houston MC, Fazio S, Chilton FH, et al. Non pharmacologic treatment of dyslipidemia. Prog Cardiovasc Dis. 2009;52:6194.
  • 6
    Plourde M, Vohl MC, Vandal M, et al. Plasma n-3 fatty acid supplement is modulated by apoE epsilon 4 but not by the common PPAR-alpha L162 polymorphism in men. Br J Nutr. 2009;102:11211124.
  • 7
    Neiminen T, Kahonen M, Viiri LE, et al. Pharmacogenetics of apoliproprotein E gene during lipid-lowering therapy: lipid levels and prevention of coronary heart disease. Pharmacogenomics. 2008;9:14751486.
  • 8
    Shih DM, Lusis AJ. Theroles of PON 1 and PON 2 in cardiovascular disease and innate immunity. Curr Opin Lipidol. 2009;20:288292.
  • 9
    Calkin AC, Tontonoz P. Genome-wide association studies identify new targets in cardiovascular disease. Sci Transl Med. 2010;2:48.
  • 10
    Djousse L, Caziano JM. Dietary cholesterol and coronary artery disease: a systematic review. Curr Atheroscler Rep. 2009;11:418422.
  • 11
    Werko L. End of the road for the diet-heart theory? Scand Cardiovasc J. 2008;42:250255.
  • 12
    Erkkila A, de Mello VD, Riserus U, Laaksonen DE. Dietary fatty acids and cardiovascular disease: an epidemiological approach. Prog Lipid Res. 2008;47:172187.
  • 13
    Weinberg SL. The diet-heart hypothesis: a critique. J Am Coll Cardiol. 2004;43:731733.
  • 14
    Mozaffarian D, Willet WC. Trans fatty acids and cardiovascular risk: a unique cardiometabolic imprint. Curr Atheroscler Rep. 2007;9:486493.
  • 15
    Chen CL, Tetri LH, Neuschwander-Tetri BA, et al. A mechanism by which dietary trans fats cause atherosclerosis. J Nutr Biochem. 2011;22:649655.
  • 16
    Siri-Tarino PW, Sun Q, Hu FB, Krauss RM. Saturated fat, carbohydrate and cardiovascular disease. Am J Clin Nutr. 2010;91:502509.
  • 17
    Otvos JD, Mora S, Shalaurova I, et al. Clinical Implications of discordance between low density lipoprotein cholesterol and particle number. J Clin Lipidol. 2011;5:105113.
  • 18
    Hodge AM, Jenkins AJ, English DR, et al. NMR determined lipoprotein subclass profile is associated with dietary composition and body size. Nutr Metab Cardiovasc Dis. 2011;21:603609.
  • 19
    Asztalos BF, Tani M, Schaefer E. Metabolic and functional of HDL subspecies. Curr Opin Lipidol. 2011;22:176185.
  • 20
    Khera AV, Cuchel M, de la Llera-Moya M, et al. Cholesterol efflux capacity, high-density lipoprotein function, and atherosclerosis. N Engl J Med. 2011;364:127135.
  • 21
    Karakas M, Koenig W, Zierer A, et al. Myeloperoxidase is associated with incident coronary heart disease independently of traditional risk factors: results form the MONICA/KORA Augsburg study. J Intern Med. 2011;271:4350.
  • 22
    Lamarche B, Tchernof A, Mooriani S, et al. Small, dense low-density lipoprotein particles as a predictor of the risk of ischemic heart disease in men. Prospective results from the Quebec Cardiovascular Study. Circulation. 1997;95:6975.
  • 23
    Kruth HS. Receptor-independent fluid-phase pinocytosis mechanisms for induction of foam cell formation with native low density lipoprotein particles. Curr Opin Lipidol. 2011;22:386393.
  • 24
    Zhao ZW, Zhu XL, Luo YK, et al. Circulating soluble lectin-like oxidized low-density lipoprotein receptor-1 levels are associated with angiographic coronary lesion complexity in patients with coronary artery disease. Clin Cardiol. 2011;34:172177.
  • 25
    Ehara S, Ueda M, Naruko T, et al. Elevated levels of oxidized low density lipoprotein show a positive relationship with the severity of acute coronary syndromes. Circulation. 2001;103:19551960.
  • 26
    Hansson GK. Inflammation, atherosclerosis, and coronary artery disease. N Engl J Med. 2005;352:16851695.
  • 27
    Harper CR, Jacobson TA. Using apolipoprotein B to manage dyslipidemic patients: time for a change? Mayo Clin Proc. 2010;85:440445.
  • 28
    Curtiss LK. Reversing atherosclerosis? N Engl J Med. 2009;360:11441146.
  • 29
    Shen GX. Impact and mechanism for oxidized and glycated lipoproteins on generation of fibrinolytic regulators from vascular endothelial cells. Mol Cell Biochem. 2003;246:6974.
  • 30
    Ridker PM, Danielson E, Fonseca FA, et al. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med. 2008;359:21952207.
  • 31
    Krishnan GM, Thompson PD. The effects of statins on skeletal muscle strength and exercise performance. Curr Opin Lipidol. 2010;21:324328.
  • 32
    Mills EJ, Wu P, Chong G, et al. Efficacy and safety of statin treatment for cardiovascular disease: a network meta-analysis of 170,255 patients from 76 randomized trials. QJM. 2011;104:109124.
  • 33
    Mammen AL, Amato AA. Statin myopathy: a review of recent progress. Curr Opin Rheumatol. 2010;22:544550.
  • 34
    Russo MW, Scobev M, Bonkovsky HL. Drug-induced liver injury associated with statins. Semin Liver Dis. 2009;29:412422.
  • 35
    Moosmann B, Behl C. Selenoproteins, cholesterol-lowering drugs, and the consequences: revisiting of the mevalonate pathway. Trends Cardiovasc Med. 2004;14:273281.
  • 36
    Liu CS, Lii CK, Chang LL, et al. Atorvastatin increases blood ratios of vitamin E/low-density lipoprotein cholesterol and coenzyme Q10/low-density lipoprotein cholesterol in hypercholesterolemic patients. Nutr Res. 2010;30:118124.
  • 37
    Wyman M, Leonard M, Morledge T. Coenzyme Q 10: a therapy for hypertension and statin-induced myalgia? Clev Clin J Med. 2010;77:435442.
  • 38
    Mortensen SA. Low coenzyme Q levels and the outcome of statin treatment in heart failure. J Am Coll Cardiol. 2011;57:1569.
  • 39
    Shojaei M, Djalali M, Khatami M, et al. Effects of carnitine and coenzyme Q 10 on lipid profile and serum levels of lipoprotein (a) in maintenance hemodialysis patients on statin therapy. Iran J Kidney Dis. 2011;5:114118.
  • 40
    Gupta A, Thompson PD. The relationship of vitamin D deficiency to statin myopathy. Atherosclerosis. 2011;215:2329.
  • 41
    Avis HJ, Hargreaves IP, Ruiter JP, et al. Rosuvastatin lowers coenzyme Q 10 levels, but not mitochondrial adenosine triphosphate synthesis, in children with familial hypercholesterolemia. J Pediatr. 2011;158:458462.
  • 42
    Kiernan TJ, Rochford M, McDermott JH. Simvastatin induced rhabdomyloysis and an important clinical link with hypothyroidism. Int J Cardiol. 2007;119:374376.
  • 43
    Nijjar PS, Burke FM, Bioesch A, Rader DJ. Role of dietary supplements in lowering low-density lipoprotein cholesterol: a review. J Clin Lipidol. 2010;4:248258.
  • 44
    Houston MC. Juice powder concentrate and systemic blood pressure, progression of coronary artery calcium and antioxidant status in hypertensive subjects: a pilot study evidence based complementary. Alternat Med. 2007;4:455462.
  • 45
    Budoff MJ, Ahmadi N, Gul KM, et al. Aged garlic extract supplemented with B vitamins, folic acid and L-arginine retards progression of subclinical atherosclerosis: a randomized clinical trial. Prev Med. 2009;49:101107.
  • 46
    Ruparelia N, Digby JE, Choudhury RP. Effects of niacin on atherosclerosis and vascular function. Curr Opin Cardiol. 2010.
  • 47
    Al-Mohissen MA, Pun SC, Frohlich JJ. Niacin: from mechanisms of action to therapeutic uses. Mini Rev Med Chem. 2010;10:204217.
  • 48
    The Coronary Drug Project Group. Clofibrate and niacin in coronary heart disease. JAMA. 1975;231:360381.
  • 49
    Taylor AJ, Lee HJ, Sullenberger LE. The effect of 24 months of combination statin and extended release niacin on carotid intima-media thickness: ARBITER 3.
  • 50
    Lee JM, Robson MD, Yu LM, et al. Effects of high dose modified release nicotinic acid on atherosclerosis and vascular function: a randomized, placebo controlled, magnetic resonance imaging study. J Am Coll Cardiol. 2009;54:17871794.
  • 51
    Taylor AJ, Villines TC, Stanek EJ, et al. Extended release niacin or ezetimibe and carotid intima media thickness. N Engl J Med. 2009;361:21132122.
  • 52
    AIM HIGH Investigators. The role of niacin in raising high density lipoprotein cholesterols to reduce cardiovascular events in patients with atherosclerotic cardiovascular disease and optimally treated low density lipoprotein cholesterol: baseline characteristics of study participants. The Atherothrombosis Intervention in Metabolic syndrome with low HDL/high triglycerides: impact on Global Health outcomes (AIM-HIGH) trial. Am Heart J. 2011;161:538543.
  • 53
    Berthold HK, Unverdorben S, Degenhardt R, et al. Effect of policosanol on lipid levels among patients with hypercholesterolemia or combined hyperlipidemia: a randomized controlled trial. JAMA. 2006;295:22622269.
  • 54
    Greyling A, De Witt C, Oosthuizen W, Jerling JC. Effects of a policosanol supplement on serum lipid concentrations in hypercholesterolemic and heterozygous familial hypercholesterolaemic subjects. Br J Nutr. 2006;95:968975.
  • 55
    Liu J, Zhang J, Shi Y, et al. Chinese red yeast rice (Monascus purpureus) for primary hyperlipidemia: a meta-analysis of randomized controlled trials. Chin Med. 2006;1:4.
  • 56
    Lu Z, Kou W, Du B, et al. Effect of Xuezhikang, an extract from red yeast Chinese rice, on coronary events in a Chinese population with previous myocardial infarction. Am J Cardiol. 2008;101:16891693.
  • 57
    Patch CS, Tapsell LC, Williams PG, Gordon M. Plant sterols as dietary adjuvants in the reduction of cardiovascular risk: theory and evidence. Vasc Health Risk Manag. 2006;2:157162.
  • 58
    Demonty I, Ras RT, van der Knaap HC, et al. Continuous dose response relationship of the LDL cholesterol lowering effect of phytosterol intake. J Nutr. 2009;139:271284.
  • 59
    Othman RA, Moghadasian MH. Beyond cholesterol lowering effects of plant sterols: clinical and experimental evidence of anti-inflammatory properties. Nutr Rev. 2011;69:371382.
  • 60
    Sabeva NS, McPhaul CM, Li X, et al. Phytosterols differently influence ABC transporter expression, cholesterol efflux and inflammatory cytokine secretion in macrophage foam cells. J Nutr Biochem. 2011;22:777783.
  • 61
    Sacks FM, Lichtenstein A, Van Horn L, et al. American Heart Association Nutrition Committee. Circulation. 2006;113:10341044.
  • 62
    Harland JI, Haffner TA. Systemic review, meta-analysis and regression of randomized controlled trials reporting an association between an intake of circa 25 g soya protein per day and blood cholesterol. Atherosclerosis. 2008;200:1327.
  • 63
    Singh DK, Banerjee S, Porter TD. Green and black tea extracts inhibit HMG-CoA reductase and activate AMP kinase to decrease cholesterol synthesis in hepatoma cells. J Nutr Biochem. 2009;20:816822.
  • 64
    Tinahones FJ, Rubio MA, Garrido-Sanchez L, et al. Green tea reduces LDL oxidability and improves vascular function. J Am Coll Nutr. 2008;27:209213.
  • 65
    Brown AL, Lane J, Holyoak C, et al. Health effects of green tea catechins in overweight and obese men: a randomized controlled cross-over trial. Br J Nut. 2011;7:110.
  • 66
    Zheng XX, Xu YL, Li SH, et al. Green tea intake lowers fasting serum total and LDL cholesterol in adults: a meta-analysis of 14 randomized controlled trials. Am J Clin Nutr. 2011;94:601610.
  • 67
    Saremi A, Arora R. The utility of omega-3 fatty acids in cardiovascular disease. Am J Ther. 2009;16:421436.
  • 68
    Rissanen T, Voutilainen S, Nyyssonen K, et al. Fish oil-derived fatty acids, docosahexaenoic acid and docosapentaenoic acid and the risk of acute coronary events: the Kuopio ischaemic heart disease risk factor study. Circulation 2000;102:26772679.
  • 69
    Davis W, Rockway S, Kwasny M. Effect of a combined therapeutic approach of intensive lipid management, omega 3 fatty acid supplementation, and increased serum 25(OH) D on coronary calcium scores in asymptomatic adults. Am J Ther. 2009;16:326332.
  • 70
    Yokoyama M, Origasa H, Matsuzaki M, et al. Japan EPA lipid intervention study (JELIS) investigators. Lancet. 2007;369:10901098.
  • 71
    Ryan AS, Keske MA, Hoffman JP, Nelson EB. Clinical overview of algal-docosahexaenoic acid: effects on triglyceride levels and other cardiovascular risk factors. Am J Ther. 2009;16:183192.
  • 72
    Kelley DS, Siegal D, Vemuri M, et al. Docosahexaenoic acid supplementation decreases remnant-like particle cholesterol and increases the (n-3) index in hypertriglyceridemic men. J Nutr. 2008;138:3035.
  • 73
    Maki KC, Dicklin MR, Davidson MH, et al. COMBination of prescription omega-3 with simvastatin (COMBOS) investigators. Am J Cardiol. 2010;105:14091412.
  • 74
    Micallef MA, Garg ML. The lipid-lowering effects of phytosterols and (n-3) polyunsaturated fatty acids are synergistic and complementary in hyperlipidemic men and women. J Nutr. 2008;138:10851090.
  • 75
    Mori TA, Burke V, Puddey IB, et al. Purified eicosapentaenoic and docosahexaenoic acids have differential effects on serum lipids and lipoproteins, LDL particle size, glucose and insulin in mildly hyperlipidemic men. Am J Clin Nutr. 2000;71:10851094.
  • 76
    Prasad K. Flaxseed and cardiovascular health. J Cardiovasc Pharmacol. 2009;54:369377.
  • 77
    Bioedon LT, Balkai S, Chittams J, et al. Flaxseed and cardiovascular risk factors: results from a double-blind, randomized controlled clinical trial. J Am Coll Nutr. 2008;27:6574.
  • 78
    Mandasescu S, Mocanu V, Dascalita AM, et al. Flaxseed supplementation in hyperlipidemic patients. Rev Med Chir Soc Med Nat lasi. 2005;109:502506.
  • 79
    Bester D, Esterhuyse AJ, Truter EJ, van Rooven J. Cardiovascular effects of edible oils: a comparison between four popular edible oils. Nutr Res Rev. 2010;23:334348.
  • 80
    Brown JM, Shelness GS, Rudel LL. Monounsaturated fatty acids and atherosclerosis: opposing views from epidemiology and experimental animal models. Curr Atheroscler Rep. 2007;9:494500.
  • 81
    Bogani P, Gali C, Villa M, Visioli F. Postprandial anti-inflammatory and antioxidant effects of extra virgin olive oil. Atherosclerosis. 2007;190:181186.
  • 82
    Covas MI. Olive oil and the cardiovascular system. Pharmacol Res. 2007;55:175186.
  • 83
    Wu WH, Kang YP, Wang NH, et al. Sesame ingestion affects sex hormones, antioxidant status and blood lipids in postmenopausal women. J Nutr. 2006;136:12701275.
  • 84
    Namiki M. Nutraceutical functions of sesame: a review. Crit Rev Food Sci Nutr. 2007;47:651673.
  • 85
    Qureshi AA, Sami SA, Salser WA, Khan FA. Synergistic effect of tocotrienol-rich fraction (TRF 25) of rice bran and lovastatin on lipid parameters in hypercholesterolemic humans. J Nutr Biochem. 2001;12:318329.
  • 86
    Song BL, DeBose-Boyd RA. Insig-dependent ubiquitination and degradation of 3-hydroxy-3 methylglutaryl coenzyme a reductase stimulated by delta-and gamma-tocotrienols. J Biol Chem. 2006;281:5461.
  • 87
    Prasad K. Tocotrienols and cardiovascular health. Curr Pharm Des. 2011;17:21472154.
  • 88
    McRae MP. Treatment of hyperlipoproteinemia with pantethine a review and analysis of efficacy and tolerability. Nutr Res. 2005;25:319333.
  • 89
    Kelly G. Pantethine: a review of its biochemistry and therapeutic applications. Altern Med Rev. 1997;2:365377.
  • 90
    Horvath Z, Vecsei L. Current medical aspects of pantethine. Ideggyogy Sz. 2009;8:220229.
  • 91
    Pins LL, Keenan JM. Dietary and nutraceutical options for managing the hypertriglyceridemic patient. Prog Cardiovasc Nurs. 2006;21:8993.
  • 92
    No Authors listed. Pantethine monograph. Altern Med Rev. 2010;15:279282.
  • 93
    Szapary PO, Wolfe ML, BLoedon LT, et al. Guggulipid for the treatment of hypercholesterolemia: a randomized controlled trial. JAMA. 2003;290:765772.
  • 94
    Ulbricht C, Basch E, Szapary P, et al. Guggul for hyperlipidemia: a review by the natural standard research collaboration. Complement Ther Med. 2005;13:279290.
  • 95
    Nohr LA, Rasmussen LB, Straand J. Resin from the Mukul Myrrh tree, guggul, can it be used for treating hypercholesterolemia: a randomized, controlled study. Complement Ther Med. 2009;17:1622.
  • 96
    Gardner CD, Lawson LD, Block E, et al. Effect of raw garlic vs commercial garlic supplements on plasma lipid concentration in adults with moderate hypercholesterolemia: a randomized clinical trial. Arch Intern Med. 2007;167:346353.
  • 97
    Soni KB, Kuttan R. Effect of oral curcumin administration on serum peroxides and cholesterol levels in human volunteers. Indian J Physiol Pharmacol. 1992;36:273275.
  • 98
    Aviram M. Atherosclerosis: cell biology and lipoproteins – oxidative stress and paraoxonases regulate atherogenesis. Curr Opin Lipidol. 2010;21:163164.
  • 99
    Fuhrman B, Volkova N, Aviram M. Pomegranate juice polyphenols increase recombinant paroxonase-1 binding to high density lipoprotein: studies in vitro and in diabetic patients. Nutrition. 2010;26:359366.
  • 100
    Avairam M, Rosenblat M, Gaitine D, et al. Pomegranate juice consumption for 3 years by patients with carotid artery stenosis reduces common carotid intima-media thickness, blood pressure and LDL oxidation. Clin Nutr. 2004;23:423433.
  • 101
    Mattiello T, Trifiro E, Jotti GS, Pulcinelli FM. Effects of pomegranate juice and extract polypyenols on platelet function. J Med Food. 2009;12:334339.
  • 102
    Aviram M, Dornfeld L, Rosenblat M, et al. Pomegranate juice consumption reduces oxidative stress, atherogenic modifications to LDL, and platelet aggregation: studies in humans and in atherosclerotic apolipoprotein E-deficient mice. Am J Clin Nutr. 2000;71:10621076.
  • 103
    Davidson MH, Maki KC, Dicklin MR, et al. Effects of consumption of pomegranate juice on carotid intima-media thickness in men and women at moderate risk for coronary heart disease. Am J Cardiol. 2009;104:936942.
  • 104
    Cesar TB, Aptekman NP, Araujo MP, et al. Orange juice decreases low density lipoprotein cholesterol in hypercholesterolemic subjects and improves lipid transfer to high density lipoprotein in normal and hypercholesterolemic subjects. Nutr Res. 2010;30:689694.
  • 105
    Di Donna L, De Luca G, Mazzotti F, et al. Statin-like principles of bergamot fruit (Citrus bergamia): isolation of 3 hydroxymethylglutaryl flavonoid glycosides. J Nat Prod. 2009;72:13521354.
  • 106
    Mollace V, Sacco I, Janda E, et al. Hypolipidemic and hypoglycaemic activity of bergamot polyphenols: from animal models to human studies. Fitotherapia. 2011;82:309316.
  • 107
    McRae MP. Vitamin C supplementation lowers serum low-density cholesterol and triglycerides: a meta-analysis of 13 randomized controlled trials. J Chiropr Med. 2008;7:4858.
  • 108
    McRae MP. The efficacy of vitamin C supplementation on reducing total serum cholesterol in human subjects: a review of 51 experimental trials. J Chiropr Med. 2006;5:212.
  • 109
    Palozza P, Simone R, Gatalano A, et al. Lycopene regulation of cholesterol synthesis and efflux in human macrophages. J Nutr Biochem. 2011;22:971978.
  • 110
    Houston M, Sparks W. Effect of combination pantethine, plant sterols, green tea extract, delta-tocotrienol and phytolens on lipid profiles in patients with hyperlipidemia. JANA. 2010;13:1520.
  • 111
    Studer M, Briel M, Leimenstoll B, et al. Effect of different anti-lipidemic agents and diets on mortality: a systemic review. Arch Int Med. 2005;165:725730.