|Year : 2013 | Volume
| Issue : 1 | Page : 26-40
Nutraceuticals in dyslipidemia management
Sunil K Kota1, Sruti Jammula2, Siva K Kota3, Surabhi Venkata Satya Krishna1, Lalit K Meher4, Epari Sanjeeva Rao5, Kirtikumar D Modi1
1 Department of Endocrinology, Medwin hospital, Hyderabad, Andhra Pradesh, India
2 Department of Pharmaceutics, Roland Institute of Pharmaceutical Sciences, Berhampur, Orissa, India
3 Department of Anesthesia, Central Security hospital, Riyadh, Saudi Arabia
4 Department of Medicine, MKCG Medical College, Berhampur, Orissa, India
5 Department of Pathology, KIMS Research & Foundation, Amalapuram, Andhra Pradesh, India
|Date of Web Publication||1-Jan-2013|
Sunil K Kota
Department of Endocrinology, Medwin Hospitals, Chiragh Ali Lane, Nampally, Hyderabad-500001, Andhra Pradesh
Source of Support: None, Conflict of Interest: It is submitted with the full knowledge and approval of our institute and there is no conflict of interest to disclose from any of the authors with regards to publication of the manuscript or an institution or product that is mentioned in the manuscript.
With the ever increasing epidemic of obesity, diabetes and hypertension among young adults, the risk of mortality and morbidity due to atherosclerotic heart disease is gradually increasing. Dyslipidemia is an additional risk factor for cardiovascular disease. Nutraceutical supplements can provide valid alternate to patients who are intolerant to statins or patients preferring alternative treatments. The combination of a lipid lowering diet and scientifically proven nutraceutical supplements can significantly reduce low density lipoprotein (LDL) cholesterol, increase LDL particle size, decreased LDL particle number decreased triglycerides and increased high density lipoprotein (HDL) particles. In addition, they address lipid induced vascular damage by suppressing inflammation, oxidative stress and immune response leading to additional antihypertension, antidiabetic properties. The current article reviews the evidence in support of different dietary supplements and their lipid lowering beneficial effects.
Keywords: Coronary heart disease, dyslipidemia, nutraceuticals
|How to cite this article:|
Kota SK, Jammula S, Kota SK, Krishna SV, Meher LK, Rao ES, Modi KD. Nutraceuticals in dyslipidemia management. J Med Nutr Nutraceut 2013;2:26-40
|How to cite this URL:|
Kota SK, Jammula S, Kota SK, Krishna SV, Meher LK, Rao ES, Modi KD. Nutraceuticals in dyslipidemia management. J Med Nutr Nutraceut [serial online] 2013 [cited 2015 Aug 1];2:26-40. Available from: http://www.jmnn.org/text.asp?2013/2/1/26/105328
| Introduction|| |
Major risk factors for atherosclerotic cardiovascular disease (CVD) include hypertension, diabetes mellitus, obesity, smoking, and dyslipidemia.  Lipids induce vascular damage by inflammation, oxidative stress, and immune dysregulation  and lead to endothelial, smooth muscle dysfunction [Figure 1]. Low density lipoprotein (LDL) is the major atherogenic lipoprotein. Other lipoprotein variables include serum total cholesterol, high density lipoprotein (HDL), and triglycerides (TG). With 1% hike in cholesterol and LDL cholesterol (LDL-C), there is increase in risk for coronary heart disease (CHD) to the tune of 2-3% and 1.2-2.0%, respectively. Similarly with 1% fall in HDL-C there is 3% increase in CHD risk.  Lifestyle changes and diet reduce CHD risk by 82%;  nutritional practices alone reduce the risk by 60%. 
|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.|
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Institution of high-carbohydrate/high-fiber diet leads to reduction of total cholesterol and LDL-C by 30% and >40%, respectively, over 4-6 weeks  and 18% after 1 year. The American diabetes association (ADA) step 1 diet with saturated fat (<10% of energy) and cholesterol (<300 mg/ day) is associated with >8% decrease in LDL-C.  The dietary approach to stop hypertension (DASH) diet  that limits consumption of saturated fats and cholesterol with increased intake of fruits and vegetables, is associated with 9% decrease in LDL-C after 8 weeks. Vegetarian diets are related to 19-29% LDL-C reduction at 4 weeks and 15% at 1 year, respectively, leading to 20-40% CAD risk reduction. , Refined carbohydrate intake is more important in changing serum lipids than saturated fats through effects on insulin resistance, atherogenic LDL, LDL particle number, very low density lipoprotein (VLDL), TGs, and total HDL and thus contributes more to CHD risk.  Many patients cannot or will not use pharmacologic treatments to treat dyslipidemia, because of side effects such as muscle disease, abnormal liver function tests, neuropathy, memory loss, mental status changes, gastrointestinal disturbances, glucose intolerance, or diabetes.  Functional foods and beverages contain specific ingredients with health benefits. Dietary supplements provide nutraceuticals in a nonfood matrix (tablet or capsule) at a dosage that exceeds the amount present in normal food.
Studies have highlighted the role of nutraceuticals in dyslipidemia. ,,, Others have reported reductions in vascular markers (carotid intima-media thickness [IMT] and obstruction, plaque progression, coronary artery calcium score by electron beam tomography [EBT], generalized atherosclerosis, and endothelial function).  The proposed mechanisms of action of nutraceutical supplements on cholesterol pathway are shown in [Figure 2]. [Table 1] depicts overview of their mechanism.
|Figure 2: Proposed mechanisms of actions of nutraceuticals and statins in the cholesterol pathway|
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Dietary fibers of plant origin are resistant to digestion. They are water soluble and structural. Soluble fiber is found in oats, psyllium, pectin, flaxseed, barley, and guar gum. The structural fibers such as cellulose, lignins, and wheat bran are insoluble. Fiber rich diets are associated with reduced CHD risk.  Soluble fibers physically bind to bile acids during the intraluminal formation of micelles, entrap cholesterol resulting in lowered cholesterol absorption.  This leads to increased bile acid synthesis, reduced hepatic cholesterol, upregulated LDL receptors, and increased LDL clearance.  They also increase intraluminal viscosity and slow macronutrient absorption  and increase satiety leading to lower energy intake.  Insoluble fiber does not have any effect on LDL-C, unless it replaces foods supplying saturated fats and cholesterol. 
Ingestion of soluble fibers 2-10 g/day leads to 5-7% reduction in LDL-C. , There is 12% and 19% reduction in risk for coronary events and coronary deaths, for each 10 g/day increment in dietary fiber.  The effect was independent of the type of soluble fiber. A dose-response relationship was noted, with an absolute lowering of LDL-C by 1.12 mg/dl/g.  Reduction in Low Density Lipoprotein-Cholesterol is is similar to that of doubling the dose of statins (approximately 6%). 
The adult treatment panel-III (ATP-III) panel recommends a daily intake of 5-10 g of soluble fiber.  Symptoms like flatulence can be minimized by using less fermented fibers like psyllium, gradual increase in dietary fibers, and drinking adequate fluids.  [Table 2] depicts the salient features of plant fibers.
Substitution of animal protein with vegetable protein appears to be associated with a lower risk of CHD. , Soy protein products also contain phytoestrogens, or isoflavones, namely genistin, glycitin, and daidzin. It is unclear whether these isoflavones or the 7S globulin fraction that is responsible for the cholesterol-lowering effect. , Soy decreases the micellar content and absorption of lipids by fiber, isoflavones, and phytoestrogens.  Soy proteins increase LDL receptor expression in human beings.  American heart association (AHA) advisory committee favors soy protein rather than soy isoflavones as the responsible nutrient, with the caveat that another yet-unknown component could be the active factor.  Soy ingestion decreases LDL significantly by 21.7 mg/dl or 12.9%.  Soy nuts (25 g soy protein) lead to 9.9% and 6.8% reduction in systolic and diastolic BP in hypertensive postmenopausal women,  possibly peptides obtained by hydrolysis of soy protein have angiotensin converting enzyme (ACE) inhibition property.  Protein hydrolysates from sesame and rice appeared to be also effective with ACE inhibition. ,
With 30-50 g soy per day, total cholesterol (TC), LDL-C, and TG decreased by 2-9.3%, 4-12.9%, and 10.5%, respectively, with 2.4% increase in HDL-C. , A dose-response relationship occurs in the range 20-106 g.  Omni Heart Trial demonstrated that partial substitution of carbohydrates with protein (mainly from nonsoy sources) lowered LDL-C by 3.3 mg/dl.  Patients with hypertriglyceridemia were shown to have reduced TGs by 14%, raised HDL-C by 5%, and exerted 6% reduction in the mean visceral fat area (-10% in individuals with visceral fat area greater than 100 cm 2 ). 
The ATP-III panel recommends soy protein as replacements for animal food products and carbohydrates or fat to enhance LDL-C lowering. , Food and drug administration (FDA) stated that 25 g/day of soy protein may reduce the risk of heart disease. 
Legumes like lupin (Lupinus albus and Lupinus angustifolius) contain up to 35-40% protein. The hypocholesterolemic effect is attributed to protein, fibers, phytosterols, and possibly others.  The decrease in plasma TG concentrations appears to depend on a downregulation of liver sterol regulatory element-binding protein (SREBP)-1c,  a transcription factor that regulates the expression of lipogenic enzymes. Dietary treatment with lupin protein significantly lowered blood pressure and reduced atherosclerosis,  because of their higher arginine content leading to increased NO production.
Other legumes investigated in the rat model of hypercholesterolemia are pea, chickpea, and faba bean: all induced a significant decrease of plasma LDL-C, baked beans and butter beans were the most potent. In addition grain legumes are nutritionally important because are valuable sources of alpha-linolenic acid (ALA).
Fish proteins increase liver LDL-R and SREBP-2 mRNA concentrations and significantly reduce cholesterolemia. However an HDL-C reduction is due to increased apo A1 mRNA expression.  In addition, ACE inhibitory peptides have been detected in fish meat hydrolyzates.
Cow milk proteins like ovokinin and ovalbumin are the main source of ACE inhibitory peptides.  The more active peptides, that is, VAP, VPP, and IPP, are also named lactotripeptides. These proteins have immune modulation, ACE inhibition, antithrombotic and antimicrobial activities.  [Table 3] depicts the beneficial effects by proteins.
Plant sterols and stanols
Among the sterols of plant origin B-sitosterol is most abundant. Others include campesterol, stigmasterol, and stenol.  Sitosterol differs from cholesterol by an additional ethyl group at C-24 leading to its poor absorption.  Vegetable oils are the main sources of phytosterols.  Phytosterols in the gut lower the micellar solubility of dietary and biliary cholesterol, lowering the amount available for absorption and increasing bile acid secretion.  They also interact with enterocyte ATP-binding cassette transport proteins (ABCG 8 and 5) to direct cholesterol back into the intestinal lumen.  They have antiinflammatory action leading to decrease in hs-CRP, interleukin (IL) 6, IL-1β, TNFα, phospholipase 2, and fibrinogen.  Phytosterols modulate signaling pathways, activate cellular stress responses, growth arrest, reduce Apo B 48 and cholesterol synthesis with suppression of HMG-CoA reductase and CYP7A1, interfere with SREBPs and promote of reverse cholesterol transport via ABCA1 and ABCG1.  Phytosterols are esterified to increase solubility and facilitate incorporation into fatty foods.  Phytosterols are hydrogenated to stanols, which are absorbed negligibly (0.02-0.3%) compared with phytosterols (0.4-5%). 
Around 2-3 g phytosterol/stanols/day lower LDL-C by 6-15%.  TC decreases by 8%, LDL decreases by 10% (range 6-15%) with no change in TGs or HDL on doses of 2-3 g/day in divided doses with meals.  A meta-analysis showed that intake of a mean 2.15 g/day of sterols reduced LDL-C by 8.8%.  When combined with statins, plant sterols additionally reduce LDL-C by 4.5-6.4%.  Some have shown reduction in atherosclerosis progression, reduced carotid IMT, and decreased plaque progression.  The plant sterols can interfere with absorption of fat-soluble vitamins and alpha carotene.  Certain hyperabsorber patients can have adverse effects of excess phytosterol.  Sitosterolemia caused by mutations in ABCG5 or ABCG8 is characterized by increased intestinal absorption (15-60%) and decreased biliary excretion of dietary sterols  leading to premature atherosclerosis.
The ATP-III panel recommends a daily intake of 2 g of plant sterol/stanol esters as a therapeutic option to enhance LDL-C lowering. 
Red yeast rice
Red yeast rice (RYR) is the fermented product of rice on which red yeast (Monascus Purpureus) has been grown. Monacus contains Monacolin K (lovastatin) that inhibits cholesterol synthesis.  RYR also contain sterols, isoflavones and monounsaturated fatty acids.
At 2400 mg/day, LDL and TG are reduced by 22% and 12%, respectively, with little change in HDL  In a meta-analysis, RYR preparations showed significant reductions in LDL-C (228.22 mg/dl).  Becker et al. evaluated the efficacy and tolerability of RYR in patients with statin-associated myalgias. In the RYR group (1800 mg/day, equivalent to lovastatin 6 mg), LDLC decreased by 35 mg/ dl.  Levels of liver enzymes, creatine phosphokinase, and pain severity scores did not differ between the groups. RYR leads to lesser depletion of mevalonate metabolites distal to HMG-CoA reductase, such as ubiquinone and GTP-binding regulatory proteins, which mediate myopathy.  A recent trial between RYR (2400 mg twice daily) versus pravastatin (20 mg twice daily) demonstrated good tolerance and comparable LDL-C lowering (30% and 27%, respectively).  RYR may be a treatment option for dyslipidemic patients intolerant to statins. Another Chinese trial revealed 10.4% decrease in frequency of major coronary events, a relative and absolute decrease of 45% and 4.7%, respectively. 
In 2001, the FDA ruled that the RYR product Cholestin was a drug and not a dietary supplement because it contained lovastatin.  It is associated with statin related adversities. Citrinin is a potential nephrotoxin produced during rice fermentation.  The recommended dose is 2400-4800 mg of a standardized RYR.
Nuts are a good source of mono- and poly-unsaturated fatty acids, and they also contain dietary fiber, phytosterols, and polyphenols. Walnuts are composed largely of poly unsaturated fatty acids (PUFAs): ALA and linoleic acid with CHD benefits.  The ratio of polyunsaturated to saturated fats in walnuts is 7.1, one of the highest among naturally occurring foods. Almonds, walnuts, hazelnuts, and pistachios have shown reductions in LDL-C.
Increased nut consumption is associated with reduced risk of CHD.  Consumption of moderate quantities of walnuts decreases LDL-C by 18.2 mg/dl.  One percent reductions in LDL-C for walnuts, pecans, peanuts, macadamias, and pistachios would be achieved with daily intakes of 4, 11, 4, 10, and 4 g, respectively.  In a recent meta-analysis, diets supplemented with walnuts resulted in a 6.7% greater decrease in LDL-C.  They can be part of a successful low-carbohydrate weight-loss program.  Consumption of 28 g of unsalted nuts daily is recommended to enhance LDL-C lowering and decrease CVD risk. 
Policosanol is a natural mixture of long-chain alipathic alcohols (mainly octocosanol) isolated and purified from sugar cane wax. Policosanol inhibits HMG-CoA reductase  and lowers LDL-C by 25%. In comparative trials with statins, policosanol showed similar or even greater improvement in lipid profiles.  There was improvement in intermittent claudication and cardiac ischemia. , However, several trials failed to confirm the cholesterol-lowering effects of policosanol.  Policosanol is currently not recommended.
Niacin includes nicotinic acid and nicotinamide. Nicotinic acid has hypolipidemic properties.  Niacin inhibits LDL oxidation, increases TG lipolysis in adipose tissue, increases Apo B degradation, reduces Apo A1 catabolism, inhibits platelet function, induces fibrinolysis, decreases cytokines and cell adhesion molecules, lowers lipoprotein(a), increases adiponectin, and is a potent antioxidant.  With 1000-4000 mg/day niacin TG, LDL-C (preferentially small dense LDL), lipoprotein (a), TG levels are reduced by 20-50%, 10-25%, and 10-30%, respectively; HDL-C levels are increased by 10-30% (preferentially HDL-2). ,,
Nicotinic acid was also the first lipid-lowering medication shown to reduce CV events with 26% and 24% reduction in nonfatal MI and cerebrovascular events.  Stockholm ischemic heart disease secondary prevention study, demonstrated a 26% and 36% reduction in mortality due to all cause and ischemic heart disease, respectively, with niacin and clofibrate.  Studies including 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, and carotid IMT.  There were 50-70% reductions in clinical events. The niacin dose should be gradually increased, administered at meal time, pretreated with 81-mg aspirin, and taken with apple pectin to reduce flushing.  The side effects of niacin include hyperglycemia, hyperuricemia, gout, hepatitis, flushing, rash, pruritus, hyperpigmentation, hyperhomocysteinemia, gastritis, ulcers, bruising, tachycardia, and palpitations. , The nonflush niacin, inositol hexaniacinate (IHN) contains six molecules of nicotinic acid esterified to one molecule of inositol. However, it is ineffective as hypolipidemic agent. [Table 4] mentions various studies on niacin.
Vitamin E is a mixture of lipid soluble phenols, tocopherols, and tocotrienols.  Tocotrienols are naturally occurring unsaturated derivative of tocopherols and have four isomers-α, β, γ, and δ, which differ in number of double bonds in the side chains.  The tocotrienols have more potent antioxidant activity than tocopherols.  Tocotrienol and tocopherol concentrates, often referred to as "tocotrienols-rich fractions" (TRFs), are obtained from rice bran or palm oil and contain about 30-50% tocopherols.  Tocotrienols are more effective in reducing LDL and TC if the concentrations of tocotrienols are high and the α tocopherols concentration is low (<20%).  Concomitant intake (<12 hour) of alpha tocopherol reduces tocotrienol absorption. The α-tocopherol competes for binding with the α-tocopherol transfer protein and interferes with transport of tocotrienols in the circulation.  Additionally α-tocopherol attenuates the inhibitory effects of tocotrienols on HMG-CoA reductase and actually induces enzymatic activity.  The absorption of tocotrienols is greater with a meal. The δ isomer is most potent.  The γ isomer is 30 times more potent than the α isomer. 
Tocotrienols have natural farnesylated analogues of tocopherols and increase the conversion of farnesyl to farnesol. Thereby it reduces conversion of farnesyl to squalene and then to cholesterol.  Farnesol signals two posttranscriptional pathways suppressing HMG-CoA reductase activity by binding the enzyme to the endoplasmic reticulum membrane proteins called INSIGS.  Number of LDL receptors increases leading to LDL removal and stimulation of apolipoprotein B degradation, clearance, and antioxidant activity. 
The gamma and delta tocotrienols lower TC by up to 17%, LDL by 24%, apo B by 15%, and lipoprotein (a) by 17% at doses of 200 mg/day of gamma and delta isomers or 100 mg/day of desmethylated derivatives given at night with food.  The combination of a statin with gamma⁄delta tocotrienols futher reduces LDL cholesterol by 10%.  Additionally the α- and δ-tocotrienols exhibit reduction in LDL oxidation and reduce carotid artery stenosis progression and the γ- and δ-tocotrienols may also reduce serum glucose. 
Oryzanol and ferulic acid in rice bran oil have both antioxidant and lipid lowering properties.  It contains unsaponifiables (up to 4.4%) including plant sterols (43%), 4 methyl sterols (10%), triterpene alcohols (29%) and less polar components such as squalene and tocotrienols (19%). Oryzanol reduces intestinal cholesterol absorption. Rice bran oil also contains 25% saturated fats, 40% PUFA, and 40% Monounsaturated fat (MUFA). Oryzanol has a greater effect on lowering plasma non-HDL-C and raising plasma HDL than ferulic acid, possibly through a greater extent to increase fecal excretion of cholesterol and its metabolites. However, ferulic acid may have a greater antioxidant capacity by its ability to maintain serum vitamin E levels. The average reduction in LDL is about 7-14%. 
Pantethine is disulfide derivative of pantothenic acid and precursor of coenzyme A (CoA). Cytoplasmic CoA stimulates oxidation of acetate at the expense of FA and cholesterol synthesis  and CoA increases Krebs cycle activity, reducing cholesterol and FA synthesis from acetate. Fatty acid and cholesterol synthesis is decreased by 50% and 80%, respectively.  Pantethine increases arterial cholesteryl esterase activity leading to removal of arterial cholesterol esters and reduces fatty streak formation and intimal, endothelial thickening, lipid deposition, LDL peroxidation, and endothelial dysfunction.  It reduces HMG-CoA reductase activity. There is reductions in TC (15%), LDL-C (20%), VLDL, TGs (36.5%), and apolipoprotein B with increased HDL-C and apolipoprotein A-1 (8%) with 300 mg TID pantethine.  In a trial of pantethine versus fibrate, fenofibrate reduced TGs better. The changes in TC and LDL were similar. When compared with bezafibrate, the changes in TGs were similar; 44.4% for bezafibrate and 37.5% for pantethine.  The recommended dose is 300 mg TID. Maximal improvement in the lipid is seen after 4 months but may improve over 9 months.
Omega-3 fatty acids
Long-chain ω-3 PUFAs such as eicosapentanoic acid (EPA) and docosahexanoic acid (DHA) (22:6) are bioactive components in oily fish. Omega-3 PUFAs alter eicosanoid biosynthesis which affects signaling, alter membrane fluidity which influences enzymatic reactions and receptor binding, and directly activate transcription factors which regulate genes affecting hyperlipidemia and inflammation.
- Apart from concentration of arachinodic acid (AA), the ratio of AA to EPA and DHA in human diets is important. Fish oil increase EPA in membrane and EPA/AA ratio leading to dampened prostanoid signaling. It mainly acts on cyclooxygenase (COX) 1 involving the production of prostaglandin D, E, and F. Platelets convert EPA to thromboxane A3 via COX-1.  EPA increases production of prostacyclin, which is platelet antiaggregatory. Increased EPA/AA ratio enhances prostaglandin E3 (PGE3) production from EPA using COX-2.  PGE3 is antiinflammatory, whereas PGE2 is proinflammatory. EPA and DHA are converted into antiinflammatory mediators: resolvins and protectins. AA to EPA or DHA ratios would shift the balance from proinflammatory prostaglandins, thromboxanes, and leukotrienes to protective resolvins and protectins.
- Omega-3 PUFAs cellular membranes influence membrane fluidity, which is important for cognitive development. They reduce platelet aggregation, blood viscosity, plasma levels of fibrinogen, PF4, and β-thromboglobulin and also increase capillary flow. 
- During inflammation, NFκB induces COX-2, TNFα, IL-6, IL-1β, and acute phase proteins. SREBP-1c controls lipogenesis. The PPARs stimulate transcription of genes for FA β-oxidation. Omega-3 PUFA can inhibit NF-kB activation, suppress SREBP- and PPAR-dependent gene transcription, leading to shift metabolism away from TG storage and toward oxidation. ,, They reduce the gene expression of IL-1α, IL-1β, TNF-α, and IL-6.
Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto (GISSI)-Prevention Study demonstrated that ω-3 PUFA supplements lowered all cause mortality, sudden cardiac death, and overall CV deaths by 20%, 45%, and 20%, respectively.  In the Nurses' Health Study and Physicians' health study there was a lower risk of CHD and sudden death with ω-3 PUFA intake. , Each 20-g/day increase in fish consumption leads to 7% reduction in fatal CHD.  The Diet and Reinfarction Trial (DART) demonstrated 29% decrease in mortality in men postMI. The Kuppio Heart Study reported 44% reduction in CHD.  Omega-3 fatty acids reduce CHD progression, coronary artery stent restenosis, and CABG occlusion and stabilize plaque.  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.  Death from CHD and sudden death is reduced by ≥25% by modest consumption of fish oil (≈250-500 mg/day of EPA and DHA).  At intakes up to 250 mg/day, the relative risk of CHD death was 14.6% lower for each 100 mg/day of EPA + DHA, for a total risk reduction of 36%, suggesting a threshold of effect around 500 mg of EPA + DHA.  Harris and von Schacky have proposed "omega-3 index" (EPA + DHA as a percentage of total red blood cell [RBC] FA) as a risk factor for death from CHD.  Levels of 8% or above are cardioprotective, and levels below 4% are associated with the increased risk for CHD.
- Cardiovascular disease. One small serving of fish per week would reduce the risk of nonfatal MI by 27% and death from CVD by 17%. Each additional serving would decrease the risk of death by a further 3.9% 
- Stroke. One small serving of fish per week would reduce the risk of stroke by 12%. Each additional serving would decrease the risk by a further 2%. 
- Children born to pregnant women who eat enough fish to get the equivalent of 1 g of DHA per day would be likely to have higher IQ scores ranging from 0.8 to 1.8 points. 
DHA and EPA (4 g/day) reduce TGs, VLDL by 45% and 50%, respectively 29% increase in antiatherogenic HDL 2b.  LDL particles number decreases and particle size increases from small type B to large type A. The rate of entry of VLDL particles into the circulation is decreased and Apo CIII is reduced, which leads to more active lipoprotein lipase. Remnant chylomicrons and lipoproteins are decreased.  They improve endothelial dysfunction; improve the AA/EPA ratio; and reduce body fat, body weight, and serum glucose. Omega-3 fatty acids are antiinflammatory and antithrombotic, lower blood pressure and heart rate, and improve heart rate variability.  Decreased fatty acid synthesis with increased fatty acid oxidation leads to weight loss. Patients are recommended to take 2-4 g of EPA + DHA (3:2) (with gammalinolenic 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). AHA recommends at least two servings of fish per week, CVD patients consume 1 g of EPA + DHA per day, and patients with hypertriglyceridemia consume 2-4 g of EPA + DHA per day. 
Monounsaturated fatty acids
MUFAs in olive oil, nuts reduce LDL by 5-10%, lower TGs by 10-15%, increase HDL by 5%, decrease oxLDL, reduce oxidation and inflammation, improve erectile dysfunction, lower blood pressure, and decrease thrombosis and CHD incidence.  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.
It is a resin extract from mukul myrrh tree (Commiphora mukul). The plant sterols E- and Z-guggulsterone act through antagonism of two nuclear hormone receptors involved in bile acid metabolism.  Guggulipids increase hepatic LDL receptors synthesis  and bile acid secretion and decrease cholesterol synthesis. Some Indian trials have reported 60-80% LDL-C lowering effect.  Szapary et al. reported 4-5% increase in LDL-C.  Controlled human clinical trials failed to show any efficacy in improving serum lipids.  Guggulipids are not recommended at this time.
Allicin is the active ingredient formed through action of alliinase enzymes on alliin. It decreases intestinal cholesterol absorption, inhibits enzymes of cholesterol synthesis including HMG-CoA reductase.  At doses of 600-900 mg/day of allicin and ajoene, there is 9-12% reduction in TC and LDL-C.  Raw garlic, powdered garlic supplement, and aged garlic extract supplement are equally efficacious. Garlic may have other protective effects with regard to CVD, such as reduced blood pressure and platelet inhibition, fibrinolytic activity, reduction in oxidized LDL, and coronary artery calcification.  Based on recent evidence garlic are not reasonably effective on the lipid profile.
Ginsenosides, a group of saponins (or glycosides) are active components of ginseng. Ginseng at doses (80-90 mg once to thrice daily) over 7 days to 3 months revealed 10% lowering of LDL-C.  Currently there are insufficient data to judge its effects.
Green tea and its active ingredient, E gallate (EGCG) reduce fasting and postprandial cholesterol levels leading to reductions in atherosclerotic CVD.  EGCG reduces gastrointestinal cholesterol absorption by interfering with the emulsification, digestion and micellar solubilization of lipids, upregulates hepatic LDL receptor, stimulates FA synthase and paroxonase, inhibits HMG-CoA reductase, stimulates mitochondrial energy expenditure, and reduces LDL oxidation.  EGCG also decreases Apo B lipoprotein secretion from cells, mimics the action of insulin, improves endothelial dysfunction, and decreases body fat.  It reduced total serum glucose and LDL-C, TGs, and free FAs and increased HDL in diabetic rats, reduced myocardial levels of lipids, and improved myocardial function.  Two cups of green tea/day in humans reduced serum LDL-C by 13 mg%, increased plasma total antioxidant activity, decreased plasma peroxides, and decreased DNA oxidative damage in lymphocytes.  A meta-analysis showed that EGCG at 224-674 mg/day reduced TC and LDL-C by 7.2 and 2.19 mg⁄dl, respectively,  with no changes in HDL or TG. The recommended dose is standardized EGCG extract of 500-700 mg/day.
It is the bioactive component of tumeric (Curcuma longa). Curcumin exhibits anticarcinogenic, antiinflammatory, antioxidative, antiinfectious, hypoglycemic, and hypocholesterolemic activities as well as activities blocking TNF, vascular endothelial growth factor (VEGF), and epithelial growth factor (EGF).  Curcumin increases the LDL receptor, slightly increases HMG-CoA reductase, and farnesyl diphosphate synthatase; increases SREBP genes and downregulates peroxisome proliferator activated receptor (PPAR), CD 36 FA translocase, and FA binding protein 1  and stimulates hepatic cholesterol-7α-hydroxylase, which increases the rate of cholesterol catabolism, liver X receptor (LXR) α expression.  Curcumin increases hepatic superoxide dismutase (SOD) and glutathione peroxidase (GSHPX) leading to reduced oxidation of LDL-C. Curcumin may aggravate bleeding in patients taking anticoagulants. Curcumin has protective effect against alcohol and PUFA induced hyperlipidemia. A significant decrease in serum lipid peroxides (33%), increase in HDLC (29%), and decrease in total serum cholesterol (11.6%) were noted.  It is recommended that patients consume about 500 mg of high quality curcumin (turmeric extracts) per day.
Chromium is a trace mineral important in glucose metabolism. Chromium potentiates the action of insulin by increasing insulin receptor-mediated signaling. Chromium is found in beer; cheese; meat; and whole grains. Supplemental chromium is best absorbed as chromium picolinate. Chromium with biotin resulted in 9.7% reduction in 2-hour glucose level, 0.54% reduction in HbA1C, and significant lowering of atherogenic index (TG/HDL).  Exposure of adipose tissue to chromium picolinate induces a loss of plasma membrane cholesterol concomitant with translocation of glucose transporter (GLUT 4) to plasma membrane. It decreases the activity of ABCA1, a transport mediator of cholesterol efflux, and upregulates SREBP.  Selected patients with Diabetes Mellitus or metabolic syndrome with concomitant dyslipidemia will have improvement in their lipid profile with chromium. Suggested intake of chromium for adults is 50-200 μg/day.
Sesame oil (Sesame indicum) is rich in both MUFA and PUFA (47% oleic acid and 39% linoleic acid). It contains lignans, sesamin, and the antioxidant compound sesaminol. Sesamin reduces serum lipid with increase in FA oxidation.  Sesamin affects the PPAR-α-mediated transcriptional events which modulate lipoprotein metabolism and inflammation. Lignans get complexed to gut cholesterol limiting its absorption. It leads to increased biliary secretion, decreased HMG-CoA reductase activity, and upregulated LDL receptor, 7 alpha hydroxylase, and SREBP 2 genes.  Postmenopausal women showed reduction of TC by 5% and LDL by 10% over 5 weeks and patients with DM and hypertension showed reductions in blood pressure, glucose, HbA1c, TC, LDL, TGs, and antioxidants.  Around 35 g/day of sesame oil should be included in the diet of dyslipidemic patients.
Probiotic bacteria ferment carbohydrates to produce short-chain FAs, which decrease serum lipids by inhibiting hepatic cholesterol synthesis and redistributing cholesterol from plasma to the liver.  Probiotics reduce lipids by coprecipitation with bile salts, deconjugation to bile salts, incorporation of cholesterol into the cellular membrane, and microbial assimilation of cholesterol. Probiotics increase antioxidant potential, lowering blood pressure, leptin, fibrinogen, F-(2) isoprostanes, and interleukin 6 and decreased monocytes adhesion to endothelial cells. Probiotic for 4-6 weeks reduces TC by 4-12%, LDL by 5-8%, and TGs by 10%.  Humans are recommended to consume a high quality mixed probiotic on a daily basis.
Fenugreek is used as treatment of DM with additional lipid-modifying and antiinflammatory, antipyretic effects. The dietary fibers glucomannan and sterol saponins lead to reduced VLDL production.  The lack of substantial human studies and animal studies refutes the effectiveness of Fenugreek for dyslipidemia.
Flax seeds contain fiber and lignans and reduce the levels of 7 alpha hydrolyase and acyl CoA cholesterol transferase (ACAT).  Flax seeds and ALA are antiinflammatory, increase endothelial nitric oxide synthase, improve endothelial dysfunction, contain phytoestrogens and decrease vascular smooth muscle hypertrophy, reduce oxidative stress, and retard development of atherosclerosis.  They reduce TC and LDL by 5-15%, lipoprotein (a) by 14%, and TG by 36%.  These effects do not apply to flax seed oil. In the Seven Countries Study, CHD was reduced with ALA consumption. The Lyon Diet Trial demonstrated that intake of flax reduced CHD and total deaths by 50-70%.  The dose required for these effects ranges from 14 to 40 g of flax seeds per day.
- Coenzyme Q is primarily used to treat statin induced myopathy. It may reduce oxidation of LDL and improve endothelial dysfunction, myocardial contractility. 
- Resveratrol reduces oxLDL; inhibits ACAT 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.  N acetyl cysteine (NAC) with similar action should be used in conjunction. The dose of trans-resveratrol is 250 mg/day and NAC is 1000 mg twice per day.
- Pomegranate increases PON 1 binding to HDL and increases PON 2 in macrophages. It is a potent antioxidant, lowers oxLDL, decreases antibodies to oxLDL, inhibits platelet function, reduces glycosylated LDL, decreases macrophage LDL uptake and lipid deposition in arterial wall, decreases progression of carotid artery IMT, and lowers blood pressure.  Consuming about 8 oz of pomegranate juice per day is recommended.
- Concentrated orange juice (750 ml/day) over 2 months decreased LDL by 11%, with reductions in Apo B and TGs and increases in HDL by 21%. The effects are due to olymethoxylated flavones, hesperitin, naringin, pectin, and essential oils. 
- Citrus bergamot (1000 mg/day) lowers LDL and TG by 36% and TG by 39 %, respectively and increases HDL by 40%. It inhibits HMG-CoA reductase; increases cholesterol and bile acid excretion; and reduces reactive oxygen species and oxLDL.  The active ingredients include naringin, neroeriocitrin, neohesperidin, poncerin, rutin, neodesmin, rhoifolin, melitidine, and brutelidine. 
- Vitamin C supplementation lowers serum LDL cholesterol and TGs. A meta-analysis found a reduction in LDL cholesterol of 7.9 mg⁄dl and TG of 20.1 mg⁄dl with 500 mg/day for 3-24 weeks; HDL did not change. 
- Lycopene inhibits HMG-CoA reductase, induce Rho inactivation, increases PPAR-α and liver X receptor activities, and reverse cholesterol transport and efflux with ABCA1 and Caveolin 1 expression. 
A combination of pantethine, plant sterols, EGCG, gamma/delta tocotrienols, and phytolens lead to reduction of TC, LDL, VLDL, and small dense LDL by 14%, 14%, 20%, and 25%, respectively.  Combination of RYR 2400-4800 mg/day and niacin 500 mg/day resulted in fall of TC, LDL, LDL particle number, and VLDL by 34%, 34%, 35%, and 27%, respectively, with 10% increase in HDL. 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.  Combining statins with omega-3 fatty acids further decreases CHD by 19%.  The combination of gamma/delta tocotrienols with a statin reduces LDL cholesterol by 10%. Plant sterols with omega-3 fatty acids have synergistic lipid-lowering and antiinflammatory effects. 
| Conclusion|| |
Dyslipidemia management includes optimal nutrition, diet combined with aerobic, and resistance exercise program. For low to moderate risk patient, nutritional supplements are the second cornerstone of therapy. In the high- and very high-risk patients, pharmacologic agents are needed. The combination of a lipid-lowering diet and selected scientifically proven nutraceutical supplements reduce LDL-cholesterol, increase LDL particle size, decrease LDL particle number, lower TG and VLDL, and increase total and type 2b HDL. Additionally inflammation, oxidative stress, immune responses, atherosclerosis, and CVD are reduced. [Table 5] provides an overview of the clinical recommendations for nutritional supplements. [Table 6] provides the fatty acid content in different oils.
|Table 6: Content of various oils. Values expressed as percent of total fat|
Click here to view
Supplements with best human data include niacin, ω-3 FAs, rice bran oil, γ-/δ- tocotrienols, pantethine, red yeast rice, plant sterols, soluble fibers, probiotics, soy, and mixed nuts with MUFA and PUFA such as almonds. Agents with insignificant effects on lipids include guggulipid, policosanol, garlic, IHN, ginseng, fenjuseek, coenzyme Q-10, and chromium. The best clinical data for reduction in CV events is with ω-3 FAs, ALA and to a lesser extent, with niacin and fiber.
| Acknowledgements|| |
All the authors extend their heartfelt thanks to Dr. Jagadeesh Tangudu, M Tech, MS, PhD, and Sowmya Jammula, M Tech, for their immense and selfless contribution toward manuscript preparation, language editing and final approval of text.
| Declaration|| |
The manuscript has been read and approved by all the authors, that the requirements for authorship as stated earlier in this document have been met, and that each author believes that the manuscript represents honest work.
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[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6]