Nutraceutical Supplements & the Management of Dyslipidemia
Nutraceutical supplement management of dyslipidemia has been infrequently reviewed.[5–6,54] New important scientific information and clinical studies are required to understand the present role of these natural agents in the management of dyslipidemia.[5–6,54] Clinical trials show excellent reductions in serum lipids and CHD with niacin, omega 3 fatty acids, red yeast rice, fiber and alpha linolenic acid. Smaller studies show improvements in various biomarkers for CVD such as inflammation, oxidative stress, vascular immune function, plaque stability, progression and regression.[5,54–55] In addition studies have used surrogate vascular markers, show improvement in arterial stiffness and improved elasticity, reduction in pulse wave velocity and augmentation index, decreased carotid intimal medial thickness (CIMT) and obstruction, coronary artery plaque progression, coronary artery calcium score by electron beam tomography (EBT) and CT angiogram as well as decrease in generalized atherosclerosis and improvement in endothelial function.[5,54–56]
The proposed mechanisms of action of some of the nutraceutical supplements on the mammalian cholesterol pathway are shown in Figure 2. Virtually all studies have shown very high safety profiles for nutritional supplements in the treatment of dyslipidemia. In the section below, all the efficacy studies, adverse effects and safety profiles will be reviewed for each nutraceutical supplement. In addition, the mechanisms of action of each supplement will be reviewed and a detailed discussion of CVD outcome data, surrogate CVD outcomes, serum biomarkers for CVD, improvements in noninvasive and invasive vascular tests will be provided where available.
Niacin (Vitamin Ref-3)
Niacin has a dose-related effect (1–4 g per day) in reducing total cholesterol (TC), LDL, apolipoprotein B (APO-B), LDL particle number, triglycerides (TG), VLDL, increasing LDL size from small type B to large type A, increasing HDL especially the protective and larger HDL 2b particle and apolipoprotein (APO-A1). Niacin may also increase the HDL particle number (the predominant protective lipid parameter) and HDL function with improvements in reverse cholesterol transport.[57–59] Niacin has a logarithmic dose response on HDL, with smaller doses having a large effect. The effect on LDL reduction is a linear dose response that requires higher doses.
The changes are dose related and vary from approximately 10–30% for each lipid level as noted above.[5,60–61] Niacin inhibits LDL oxidation, increases TG lipolysis in adipose tissue, increases APO-B degradation, reduces the fractional catabolic rate of HDL-APOA-1, inhibits platelet function, induces fibrinolysis, decreases cytokines and cell adhesion molecules (CAMs), lowers Lp(a), increases adiponectin, which provides antioxidant activity, inhibits CETP and increases reverse cholesterol transport.[5,57–61] However, despite an improved lipid profile, there is a variable improvement in endothelial and microvascular function.
Randomized clinical trials such as the Coronary Drug Project, HATS trial, ARBITOR 2, Oxford Niaspan Study, FATS, CLAS I and CLAS II and AFRS have shown reduction in coronary events, decreases in coronary atheroma (plaque) and decreases in carotid IMT.[5,60–66] The recent negative findings in the AIM HIGH study[67,68] do not detract from these positive clinical trials, as this study has numerous methodological design flaws and was not powered to statistically determine CVD end points.
The recent THRIVE trial of 26,000 patients using 2 g of extended release niacin plus the antiflushing agent laropiprant daily or placebo on top of a background therapy of simvastatin with or without ezetimibe did not reduce cardiovascular events despite an increased HDL of 17% and decreased LDL of 20%.[69,70] Whether the inhibition of flushing by laropiprant or some other unknown effect of this agent interfered with the HDL function and the CV outcomes is not clear. However, the recommendation by some not to use niacin in face of the other many positive studies is clearly premature and incorrect. The effective dosing range is from 500 to 4000 mg per day. Only vitamin ref-3 niacin is effective in dyslipidemia. The nonflush niacin (inositol hexanicotinate) does not improve lipid profiles, and is not recommended..[5,71] The side effects of niacin include hyperglycemia, hyperuricemia, gout, hepatitis, flushing, rash, pruritus, hyperpigmentation, hyperhomocysteinemia, gastritis, ulcers, bruising, tachycardia and palpitations.[5,60–61] Elevations in homocysteine should be treated with vitamin ref-6, ref-12 and folate. Niacin-induced flushing is minimized by increasing the dose gradually, taking on a regular basis without missing doses, taking with meals, avoiding alcohol within 4 h of ingestion of niacin, consumption of 81-mg baby aspirin and supplemental quercetin, apples or apple pectin or sauce.
Policosanol is a sugar cane extract of eight aliphatic alcohols that has undergone extensive clinical studies with variable results. Most of the earlier studies that showed positive results performed in Cuba have been questioned as to their validity.[5,54,72–73] 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.[5,54,72–73]
Red Yeast Rice
Red yeast rice (RYR; Monascus Purpureus) is a fermented product of rice that contains monocolins, which inhibit cholesterol synthesis via HMG CoA reductase and thus has 'statin-like' properties (13 natural statins).[5,54,74–96] RYR also contains ergosterol, amino acids, flavonoids, trace elements, alkaloids, sterols, isoflavones and monounsaturated fatty acids that improve the lipid profile. RYR administered orally to adults subjects with dyslipidemia at 2400 mg per day reduced LDL-C by 22% (p < 0.001), TG by 12% with little change in HDL.[5,54,74] RYR reduces the risk of abdominal aortic aneurysms by suppressing angiotensin II levels. RYR also is effective in mouse models against obesity-related inflammation, insulin resistance and nonalcoholic fatty liver disease. RYR in conjunction with berberine improves insulin resistance, glucose and lipids in subjects with or without metabolic syndrome.[86,89,95] RYR, policosanol and artichoke leaf extract decrease LDL-C significantly[77,84] as did RYR with plant stanols. RYR with berberine, policosanol, astaxanthin, coenzyme Q10 and folic acid reduce LDL-C by 21.1% similar to pravastatin 10 mg per day with a 4.8% increase in HDL-C over 8 weeks.
RYR inhibits TNF-α and MMP-2 and MMP-9 (metalloproteinases), suppresses caveolin-1, increases eNOS (endothelial nitric oxide synthase) expression, improves abnormal hemorheology, increases adiponectin, improves the leptin-to-adiponectin ratio, lowers HS CRP (high sensitivity CRP) and improves vascular remodeling parameters such as MMP-2 and MMP-9, reduces expression of tissue factor, ox-LDL and reduces thrombosis in animal models by suppressing NADPH oxidase and extracellular signal-regulated kinases activation. In a recent placebo-controlled Chinese study of 5000 subjects over 4.5 years, an extract of RYR reduced LDL 17.6% (p < 0.001) and increased HDL 4.2% (p < 0.001). CV mortality fell 30% (p < 0.005) and total mortality fell 33% (p < 0.0003) in the treated subjects. The overall primary end point for MI and death was reduced by 45% (p < 0.001). Recent meta-analysis and clinical trials of RYR for dyslipidemia and CVD end points confirmed these positive findings.[81,82,93–94] A highly purified and certified RYR must be used to avoid potential renal damage induced by a mycotoxin, citrinin.[5,54,74] The recommended dose is 2400–4800 mg/day of a standardized RYR. No adverse effects have been reported such as myalgias or liver dysfunction with long term use nor is there any interference with the CYP450 enzymes. Although reductions in coenzyme Q 10 may occur in predisposed patients and those on prolonged high dose RYR, due to its weaker 'statin-like' effect this is not as likely as with statins. RYR is an excellent alternative to patients with statin-induced myopathy[5,54,74,88,96] and in statin-intolerant patients with or without Type 2 DM in conjunction with the Mediterranean diet to effectively manage their dyslipidemia.
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 saturated stanols.[5,54,97–101] The plant sterols are much better absorbed than the plant stanols. The daily intake of plant sterols in the USA is approximately 150–400 mg per day mostly from soybean oil, various nuts and tall pine tree oil. These have a dose-dependent reduction in serum lipids. Total cholesterol is decreased 8%, LDL is decreased 10% (range: 6–15%) with no change in TG and HDL on doses of 2–3 grams per day in divided doses with meals.[5,54,97–101] 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. The mechanism of action is primarily to decrease the incorporation of dietary and biliary cholesterol into micelles due to lower 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 ABCG5) that directs cholesterol back into the intestinal lumen.[5,54,97] 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. The plant sterols are also anti-inflammatory and decrease the levels of proinflammatory cytokines such as hsCRP, IL-6, IL1b, TNF-α, PLA 2 and fibrinogen, but these effects vary among the various phytosterols.[101,102] 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 SREBP and promotion of reverse cholesterol transport via ABCA1 and ABCG1. The biological activity of phytosterols is both cell type and sterol specific.
The plant sterols can interfere with absorption of lipid-soluble compounds such as fat soluble vitamins and carotenoids like vitamin D, E, K and α-carotene.[5,54] Some studies have shown reduction in atherosclerosis progression, reduction in progression of carotid IMT and carotid plaque but the results have been conflicting.[5,54] Patients that 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. This is a rare autosomal recessive disorder termed sitosterolemia. There are no studies on CHD or other CVD outcomes to date with phytosterols. The recommended dose is approximately 2–2.5 g per day (average 2.15 g per day).
Numerous studies have shown mild improvements in serum lipids with soy at doses of about 30–50 g per day.[5,54,103–104] Total cholesterol falls 2–9.3%, LDL decreases 4–12.9%, TG decreases 10.5% and HDL increases up to 2.4%. However, the studies are conflicting owing to differences in the type and dose of soy used in the studies, as well as nonstandardized methodology.[5,54,103–104] Soy decreases the micellar content and absorption of lipids through a combination of fiber, isoflavones (genistin, glycitin and diadzin) and phytoestrogens.[5,54,103–104] Soy also reduces SREBP, HMG-COA reductase, increases LDL receptor density and increases the antioxidant activity of SOD and catalase. The greatest reduction is seen with soy-enriched isoflavones with soy protein. Fermented soy is preferred.
Green Tea Extract & Green Tea (EGCG)
Catechins, especially EGCG, may improve the lipid profile by interfering with micellar solubilization of cholesterol in the GI tract and reduce absorption. In addition, EGCG reduces the fatty acid gene expression, inhibits HMG CoA reductase, increases mitochondrial energy expenditure, reduces ox-LDL, increases PON-1, upregulates the LDL receptor, decreases APO-B lipoprotein secretion from cells, mimics the action of insulin, improves endothelial dysfunction, activates Nrf2, increases HO-1 expression, decreases inflammation, displaces caveolin-1 from cell membranes, increases nitric oxide, reduces endothelial inflammation and decreases body fat.[5,106–109]
A meta-analysis of human studies of 14 trials show that EGCG at 224–674 mg per day or 60 oz of green tea per day reduced TC 7.2 mg/dl and LDL 2.19 mg/dl (p < 0.001 for both). There was no significant change in HDL or TG levels. The recommended dose is a standardized EGCG extract at 500–1000 mg per day.
Omega 3 Fatty Acids
Observational, epidemiologic and controlled clinical trials have shown significant reductions in serum TG, VLDL, decreased LDL particle number and increased LDL and HDL particle size as well as major reductions in all CVD events.[5,111–118] The DART trial demonstrated a decrease in mortality of 29% in men post MI and the 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 subjects in the highest quintile of omega 3 intake compared with the lowest quintile.[5,111–112] Omega 3 FA reduce CHD progression, stabilize plaque, reduce coronary artery stent restenosis and CABG occlusion.[5,113] In the JELIS study, the addition of 1.8 g of omega EPA to a statin resulted in an additional 19% RRR in major coronary events and nonfatal MI and a 20% decrease in CVA.[5,114]
There is a dose-related reduction in VLDL of up to 50%, TG of up to 50%, with little to no change or decrease in total TC, LDL, APO B and no change to slight increase in HDL.[5,115–118] 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 is also increased by up to 29%. The rate of entry of VLDL particles into the circulation is decreased and APOCIII is reduced, which allows lipoprotein lipase to be more active. There is a decrease in remnant chylomicrons and remnant lipoproteins.[5,116] Patients with LDL over 100 mg/dl have reductions in total LDL and those that are below 80 mg/dl have mild increases. 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 FA are anti-inflammatory, antithrombotic, lower BP and heart rate, improve heart rate variability,[5,111] decrease fatty acid synthesis, increase in fatty acid oxidation and reduce body fat and weight. Omega 3 fatty acids are one of the only substances that lower Lp-LPA2. Insulin resistance is improved and there are no significant changes in fasting glucose or hemoglobin A1C with long-term treatment. Doses of 3 g per day of combined EPA and DHA at a 3:2 ratio with GLA at 50% of the total EPA and DHA content and 700 mg of γ/δ tocopherol at 80 and 20% α-tocopherol per 3 g of DHA and EPA are recommended. DHA and EPA may have variable but favorable effects on the various lipid levels.[5,115–116,119] EPA does not usually increase LDL, is less effective in lowering TG than DHA and does not alter the LDL and HDL particle size. Although DHA may increase total LDL, it increases LDL and HDL size and lowers TG more. The combination of plant sterols and omega 3 fatty acids is synergistic in improving lipids and inflammation. New free fatty acid forms of omega 3 fatty acids have a fourfold greater area under the plasma n-3 PUFA curve than prescription Lovaza and thus a more potent reduction in TG levels. The data of krill oil on dyslipidemia is limited to only two studies in humans.[120,121] The first study showed a dose-related response of LDL-C reduction up to 39%, TG reduction of 27% and HDL elevation of 60%. Another study showed minimal reductions in TG of 10%, but the decrease was not sustained during long-term treatment. These findings with krill oil are very disparate and the studies are not confirmatory. Krill oil is not recommended at this time for the treatment of dyslipidemia.
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 5–15%, Lp(a) by 14%, TG by up to 36% with either no change or a slight reduction in HDL.[5,122–124] These properties do not apply to flax seed oil. In the Seven Countries study CHD was reduced with increased consumption of ALA. In the Lyon diet trial at the end of 4 years, intake of flax reduced CHD and total deaths by 50–70%. Flax seeds contain fiber, lignins and phytoestrogens and decrease the levels of 7-α-hydroylase and acyl CoA cholesterol transferase.[5,122–124] Flax seeds and ALA are anti-inflammatory, reduce HS-CRP, decrease TG, increase HDL, decrease insulin resistance and risk of Type 2 DM, reduce visceral obesity and systolic BP, increase eNOS and improve endothelial dysfunction. Flax decreases vascular smooth muscle hypertrophy, reduces oxidative stress, increases cholesterol efflux in macrophage-derived foam cells by decreasing stearoyl CoA desaturase-1 expressions and farnesoid X receptor's mechanisms of action which, retard the development of atherosclerosis..[5,122–126] The dose required for these effects is between 14 to 40 grams of flax seed per day.[5,122–126] Chia seeds (Salvia hispanica) are the richest botanical source of ALA at 60% weight/volume. The dose of Chia seeds is 25 g per day.
Monounsaturated fats (MUFA) such as olives, olive oil and nuts reduce LDL by 5–10%, lower TG 10–15%, increase HDL 5%, decrease ox-LDL, reduce oxidation and inflammation, improve ED, lower BP, decrease thrombosis and reduce the incidence of CHD (Mediterranean diet).[5,127–131] MUFA reduces CD40L gene expression and its downstream products (IL23a, adrenergic B-2 receptor, ox-LDL receptor 1 and IL-8 receptor) and related genes involved in atherogenic and inflammatory process in vivo in humans. MUFA are one of the most potent agents to reduce ox-LDL in humans. The equivalent of three to four tablespoons (30–40 g) per day of extra virgin olive oil (EVOO) in MUFA content is recommended for the maximum effect in conjunction with omega 3 fatty acids. The caloric intake of this amount of MUFA did not result in any weight gain in the PREDIMED study and resulted in a significant reduction in CVD.
Sesame at 40 g per day reduces LDL by 9% through inhibition of intestinal absorption, increasing biliary secretion, decreasing HMG CoA reductase activity, upregulating the LDL receptor gene expression, 7-α-hydroxylase gene expression and the SREBP 2 gene expression.[133,134] A randomized placebo controlled crossover study of 26 postmenopausal women who consumed 50 gof sesame powder daily for 5 weeks had a 5% decrease in total cholesterol and a 10% decrease in LDL-C.
Tocotrienols are a family of unsaturated forms of vitamin E termed α, β, γ and δ. The γ- and δ-tocotrienols lower TC up to 17%, LDL 24%, APO B 15%, and Lp(a) 17% with minimal changes in HDL or APO-A1 in 50% of subjects at doses of 200 mg per day given at night with food.[5,135–137] The γ/δ form of tocotrienols inhibits cholesterol synthesis by suppression of HMG-CoA reductase activity by two post-transcriptional actions.[5,135–137] 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 called INSIGS. The tocotrienols have natural farnesylated analogs of tocopherols that give them their effects on HMG CoA reductase. In addition, the LDL receptor is augmented and they exhibit antioxidant activity.
The tocotrienol dose is very important, as increased dosing will induce its own metabolism and reduce effectiveness, whereas lower doses are not as effective. Also concomitant intake (less than 12 h) of α-tocopherol reduces tocotrienol absorption. Increased intake of alpha tocopherol over 20% of total tocopherols may interfere with the lipid-lowering effect.[5,135]
Tocotrienols are metabolized by successive β-oxidation then catalyzed by the CYP450 enzymes 3A4 and CYP4F2. The combination of a statin with γ/δ tocotrienols further reduces LDL cholesterol by 10%. The tocotrienols block the adaptive response of upregulation of HMG-CoA reductase secondary to competitive inhibition by the statins.[5,135] Carotid artery stenosis regression has been reported in approximately 30% of subjects given tocotrienols over 18 months. They also slow progression of generalized atherosclerosis.[5,137] The recommended dose is 200 mg of γδ tocotrienol at night with food.
Pantethine is the disulfide derivative of pantothenic acid and is metabolized to cystamine-SH which is the active form in treating dyslipidemia.[5,138–142] Over 28 clinical trials have shown consistent and significant improvement in serum lipids. TC is decreased 15%, LDL by 20%, APO B by 27.6%, and TG by 36.5% over 4–9 months. HDL and APO A1 are increased 8%.[5,138–143] The effects on lipids are slow with peak effects at 4 months but may take up to 6- 9 months.[5,138–143] In addition, pantethine reduces lipid peroxidation of LDL, decreases lipid deposition, intimal thickening and fatty streak formation in the aorta and coronary arteries.[5,138–143] Pantethine inhibits cholesterol synthesis and accelerates 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 the Krebs cycle activity.[5,138–143] In addition, cholesterol esterase activity increases and HMG-CoA reductase activity decreases.[5,138–143] There is 50% inhibition of FA synthesis and 80% inhibition of cholesterol synthesis. Its lipid effects are additive to statins, niacin and fibrates. The recommended effective dose is 300 mg three-times per day or 450 mg twice per day with or without food.[5,138–143]
Guggulipids (Commiphora mukul) are resins from the mukul myrrh tree that contain active lipid-lowering compounds called guggulsterones.[5,144–146] These increase hepatic LDL receptors, bile acid secretion and decrease cholesterol synthesis in animal experiments.[5,144] However, controlled human clinical trials have not shown these agents to be effective in improving serum lipids.[144–146] One study of 103 subjects on 50–75 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 Lp(a) and HS- CRP. Guggulipids are not recommended at this time to treat dyslipidemia.
Numerous placebo-controlled clinical trials and meta-analysis in humans show reductions in TC of 17 ± 5 mg/dl and reductions of LDL of about 9 ± 6 mg/dl at doses of 600–900 mg per day over 2 months with a standardized extract of allicin and ajoene.[5,147–154] Many studies have been poorly controlled and use variable types and doses of garlic, which have given inconsistent results.[5,147–148] Aged garlic (AGE) has shown the best results related to improvement in serum lipids as well as lowering BP, improving endothelial function and arterial elasticity, decreasing coronary artery calcium and plaque progression, and lowering HSCRP.[5,55,147–154] Garlic reduces intestinal cholesterol absorption, inhibits enzymes involved in cholesterol synthesis and deactivates HMG COA reductase.[5,147] In addition, aged garlic reduces vascular smooth muscle proliferation and transformation, decreases oxidative stress and inflammation, decreases ox-LDL, prevents entry of lipids into the arterial wall and macrophages, increases eNOS and NO, increases glutathione, glutathione reductase and superoxide dismutase, has fibrinolytic activity and antiplatelet activity.[5,55,147] Aged garlic has been used in these studies alone or in conjunction with B vitamins, folate, arginine and statins.[148–151] The preferred dose of aged garlic (Kyolic garlic) is 600 mg twice per day.
Resveratrol reduces ox-LDL, inhibits ACAT activity and cholesterol ester formation, increases bile acid excretion, reduces TC, TG and LDL, increases PON-1 activity and HDL, inhibits NADPH oxidase in macrophages and blocks the uptake of modified LDL by CD36 SR (scavenger receptors).[155,156] N Acetyl Cysteine (NAC) has this same effect on CD 36 DR and should be used in conjunction with resveratrol. The dose of trans-resveratrol is 250 mg per day and NAC is 1000 mg twice per day.
Curcumin, phenolic compound in tumeric and curry,[5,157] induces changes in the expression of genes involved in cholesterol synthesis such as the LDL receptor mRNA, HMG CoA reductase, SREBP, cholesterol 7-α-hydrolyze, PPAR, LXR, affects the expression of genes involved in leukocyte adhesion and transdendothelial migration to inhibit atherosclerosis.[5,157–160] In one human study of ten patients consuming 500 mg per day of curcumin, the HDL increased 29% and total cholesterol fell 12%.[5,157] A recent meta-analysis of five studies of 133 subjects did not indicate a significant effect of curcumin on any of the lipid parameters. Larger randomized clinical trials are needed to determine the lipid-lowering effects and potential reduction in CV effects with curcumin.
Pomegranate increases PON-1 binding to HDL and levels of PON-2 in macrophages. It is a potent antioxidant that increases total antioxidant status, lowers ox-LDL, decreases antibodies to ox-LDL, inhibits platelet function, reduces glycosylated LDL, decreases macrophage LDL uptake and reduces lipid deposition in the arterial wall.[161–166] These changes impede the progression of carotid artery IMT and lower blood pressure especially in subjects with the highest oxidative stress, known carotid artery plaque and the greatest abnormalities in TG and HDL levels.[161–166] Consuming about 8 oz of pomegranate juice per day or one to two cups of pomegranate seeds is recommended.
In one human study, 750 ml of concentrated orange juice per day over 2 months decreased LDL 11% with reductions in APO B, TG and increased HDL by 21%. The effects are due to polymethoxylated flavones, hesperitin, naringin, pectin and essential oils. Additional studies are needed to verify this data.
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%, TG 39% and increases HDL 40%.[168–171] Citrus bergamot inhibits HMG CoA reductase, increases cholesterol and bile acid excretion, binds to the ACAT receptor, and lowers ox-LDL.[168–171] Favorable effects on glycemic parameters include reductions in glucose via AMPK and GLUT 4 receptor reduction in ROS and weight loss. The active ingredients include naringin, neroeriocitrin, neohesperidin, poncerin, rutin, neodesmin, rhoifolin, melitidine and brutelidine.[168–171]
Clin Lipidology. 2014;9(3):333-354. © 2014 Future Medicine Ltd.