Table 1.
Nutraceuticals and their LDL-Lowering Effects.
| Nutraceutical | Class | Level of Evidence | Mechanism of Action | Daily Dose | Lipid Lowering Effect | Safety | Drug Interactions |
|---|---|---|---|---|---|---|---|
| Anthocyanins | IIb | A | Downregulates the mRNA of SREBP-1c and fatty acid synthase, resulting in less fat accumulation in adipocytes [17] | 100 to 450 mg [18] | LDL-C: −5 to −10% [16] | Well tolerated [16] Precautions during pregnancy (polyhydramnios) [19] | No known drug interactions [16] |
| Artichoke Leaf Extract | IIa | A | Inhibit HMG-CoA reductase [16,20], induce pathways involving SREBP and ACAT, [20] increase excretion of bile acids [21] |
500 to 2800 mg [21] | LDL-C: −5 to −15% [16] | GI discomfort, skin reactions, and asthma exacerbations [16,22] Insufficient data in pregnant or breastfeeding patients [22] | Antidiabetic drugs, antihypertensive drugs, and CYP2B6 and CPY2C19 inducers and inhibitors [22] |
| Berberine | I | A | PCSK9-I [23], upregulates the hepatic LDL receptor by activing the Jun amino-terminal kinase and extracellular signal regulated kinases [16,24] Decreased GI reabsorption of cholesterol, enhanced fecal excretion, increased hepatic bile acid formation, [25] activates AMPK, [26,27] inhibits NADPH [28] |
200 to 1500 mg [29] | LDL-C: −15 to −20% [16] | GI symptoms, headaches, and elevated transaminases [30,31] No serious liver injury [16,29,31] Kernicterus in infants [31] Pregnant women, breastfeeding mothers, and infants should avoid [22] |
Anticoagulants, anti- platelets, antidiabetic drugs, antihypertensive drugs, central nervous system depressants, cyclosporine, CYP substrates (CYP2C9, CYP2D6, CYP3A4), dextromethorphan, and tacrolimus [22] |
| Bergamot | IIa | A | Inhibits HMG-CoA reductase, ACAT [16] pancreatic cholesterol ester hydrolase, [32] activates AMPK, [26] radical-scavenging activity, [16] increases fecal excretion of bile acids [16,33] | 200 to 1500 mg [16] | LDL-C: −7 to −40% [34] | GI discomfort and muscle cramps Little safety data in patients who are pregnant or breastfeeding [22] | Antidiabetic drugs due to hypoglycemia [22] |
| L-carnitine | IIb | A | Decreases TG synthesis by decreasing available free fatty acids, increases mitochondrial oxidation of long chain fatty acids, and increases production of apolipoprotein A1 [35] | 500 mg to 6 g [35] |
LDL-C: −0.14 mmol/L; 95% CI, –0.22 to −0.06 TG: −0.11 mmol/L; 95% CI, –0.18 to −0.03 [35] |
Fishy body odor, minor nausea, or GI discomfort [22,36] Safe in patients who are pregnant or breastfeeding Parenteral carnitine supplementation is safe in infants [22,37,38] | Thyroid hormones and warfarin [22] |
| Chromium | III | A | Upregulates gene expression of PPAR-γ and LDL receptor [39] | 40 to 1000 mcg [39] | TC: −0.17 mmol/L; 95% CI, –0.27 to −0.07 [40] | Weight loss, hypoglycemia, anemia, thrombocytopenia, elevated transaminases, elevated creatinine, rhabdomyolysis, and dermatitis Safe during pregnancy and in women breastfeeding [41] |
Levothyroxine, insulin, metformin, and other anti- diabetic medication [41] |
| Chitosan | IIb | A | Interferes with GI absorption by binding to negatively charged fatty acids and bile acids and disrupting the emulsification of neutrally charged cholesterol [42] | 0.3 to 3 g [43] | LDL-C: −5% [16] | Should not be used in patients with allergies to crustaceans or shellfish [42] GI discomfort Insufficient data on use in patients who are pregnant or breastfeeding [22] |
Acyclovir or warfarin [22] |
| Coenzyme Q10 | III | A | Reduce oxidative stress and restores coenzyme Q10 [44] | 30 to 250 mg [45] | TG: −0.0032 mmol/L; 95% CI, –0.0063 to −0.0001 [45] HDL-C: 0.03 mmol/L; 95% CI, 0.01 to 0.06 [46] |
Insomnia, GI discomfort, dizziness, headache, dyspepsia, photophobia, irritability, and fatigue [47] | Anticoagulants, insulin, and cancer treatments Beta-blockers can inhibit enzyme reactions involving coenzyme Q10 [47] |
| Conjugated Linoleic Acid | IIb | A | Promotes cholesterol efflux by increasing expression of ABCA1 and ABCG1 [48] | 0.5 to 7 g [49] | LDL-C: −5% [16] | GI discomfort, hepatotoxicity [50] Safe in patients who are pregnant [51] Insufficient data in patients breastfeeding [22] | Anticoagulants, anti- platelet drugs, and antihypertensives [22] |
| Curcumin | IIb | A | Inhibits intestinal NPC1L1 cholesterol transporter expression by inhibiting the SREBP2 transcription factor, [52] downregulates PCSK9 expression, [53] upregulates ABCA1 expression [54] | 50 mg to 6 g [55] | LDL-C: −5% [16] | GI discomfort [22,56] Precautions in patients who are pregnant or breastfeeding as levels greater than dietary levels may be unsafe [22] | Alkylating agents, amlodipine, anticoagulants, anti- platelets, antidiabetic drugs, CYP3A4 substrates, sulfasalazine, tacrolimus, talinolol, tamoxifen, and warfarin [22] |
| Soluble Fiber | |||||||
| Glucomannan | IIa | A | Inhibits HMG-CoA reductase, reduces GI cholesterol absorption, [57] increases the conversion of bile acids into cholesterol through increased 7-α- hydroxylase activity [16] | 1 to 15 g per day [16,58] | LDL: −0.35 mmol/L; 95% CI, –0.46 to −0.25 [58] |
GI discomfort, obstructions in the bowel or esophagus, [22,58] reduce absorption of vitamin E Insufficient data in patients who are pregnant or breastfeeding [22] | May be issues with absorption of medicines [22] |
| β-Glucan | IIa | A | Viscosity reduces cholesterol absorption, increases bile acid excretion [59] | 3 to 25 g [16,60] | LDL-C: −0.27 mmol/L; 95% CI, −0.35 to −0.20 [60] | Insufficient data in patients who are pregnant or breastfeeding [22] | antihypertensives and immunosuppressant drugs [22] |
| Guar Gum | IIa | A | Prevents GI cholesterol absorption, increases bile acid extraction [61] | 30 to 100 g [61] | LDL-C: −0.45 mmol/L; 95% CI, –0.61 to −0.29 [61] | GI discomfort, obstruction of the esophagus or bowel [22,61] Safe during pregnancy as it treats intrahepatic cholestasis of pregnancy [62] Insufficient data in patients who are breastfeeding [22] |
Penicillin, metformin, estradiol, and digoxin May inhibit the absorption of oral drugs [22] |
| Psyllium | IIa | A | Reduces GI absorption cholesterol, binds to bile acids [63] | 2 to 20 g per day [63] | LDL-C: −0.33 mmol/L; 95% CI, –0.38 to −0.27 [63] | GI discomfort, mild anaphylactic allergic reactions, bowel obstructions, and esophageal obstructions [16,22,64] Safe during pregnancy or while breastfeeding [65] |
Carbamazepine, digoxin, estradiol, lithium, metformin, and olanzapine [22] |
| Garlic Extract | IIa | A | Inhibits HMG-CoA reductase, acetyl-CoA synthetase, squalene- monooxygenase, and potentially non- acetylated CoA, [66] GI absorption of fatty acids and cholesterol, increases the excretion of bile acids [16] | 0.3 to 20 g [16,67] | LCL-C: −5 to −10% [16] | GI symptoms, body odor, garlicy breath, aftertaste, and increased bleeding risk [16,68] Possibly unsafe when used in higher levels in patients who are pregnant or breastfeeding [22] |
Anti-hypertensive drugs, anti-diabetic drugs, atazanavir, CYP2E1/CYP3A4 inducers and inhibitors, isoniazid, protease inhibitors, saquinavir, tacrolimus, and warfarin [22] |
| Green Tea | IIa | A | Inhibits expression of nitric oxide synthase, [69] activates AMPK, inhibits HMG-CoA reductase, [16,69] inhibits the reabsorption of bile acids [16,70] | 100 mg to 20 g per day [16,69] | LCL-C: −5 [16] | GI discomfort, transitory blood pressure elevations, rashes thrombotic thrombocytopenic purpura, hepatotoxicity, hypokalemia, [16,22,69] Higher doses associated with iron and folate deficiency; use with precaution in pregnant patients [16,71] |
5-fluorouracil, adenosine, anti- coagulants, anti- platelets, antidiabetic drugs, statins, beta agonists, bortezomib, carbamazepine, cimetidine, clozapine, lisinopril, lithium, stimulants, verapamil, and valproate acid [22] |
| Alpha Lipoic Acid | IIb | A | Modulates fat synthesis, mitochondrial β- oxidation of fat, clearance of TG-rich lipoproteins in the liver, and adipose TG accumulation [72] | 300 to 1800 mg [73] | LDL-C: −0.28 mmol/L; 95% CI, −0.50 to −0.06 [73] | GI discomfort, skin rash, and rarely insulin autoimmune syndrome Safe during pregnancy [74] Insufficient data in patients breastfeeding [22] | Alkylating agents, anticoagulants, anti- platelet drugs, antidiabetic drugs, antitumor antibiotics, and levothyroxine [22] |
| Lupin Protein | IIa | A | Inhibits HMG-CoA receptor and PCSK9 activity. Refs. [75,76], upregulates SREBP-2 via phosphatidylinositol-3- kinase, alpha serine/threonine-protein kinase, and glycogen synthase kinase-3 beta kinase pathways [77] | ≤35 g [78] | LDL-C: −5 to −12% [16] | GI discomfort Likely safe to use in patients who are pregnant or breastfeeding [22] | No known interactions with drugs [22] |
| Magnesium | III | A | Regulates HMG-CoA reductase expression, upregulates cholesterol 7α-hydroxylase and LCAT expression [79] | 35 to 500 mg [80] | LDL-C: −0.18 mmol/L; 95% CI, –0.30 to −0.05 [81] | GI discomfort, flushing, confusion, hypotension, hyperreflexia, respiratory depression, hyperkalemia, hypocalcemia, pulmonary edema, and cardiac arrest [82,83] Safe during pregnancy at appropriate doses [22,83] Appears safe to use during breastfeeding [22] |
Aminoglycosides, antacids, bisphosphonates, calcium channel blockers, digoxin, ketamine, levodopa, carbidopa, potassium-sparing diuretics, quinolones, sulfonylurea, and tetracyclines [22] |
| Niacin | IIb | A | Inhibits diacylglycerol acyltransferase-2, which decreases TG synthesis and LDL-C by increasing hepatic apoB degradation, raises HDL-C by stimulating hepatic apolipoprotein A-I production [84] | ≤2 g daily [85,86] | TG: −28.6%; LDL-C: −12.0% [86] | GI hemorrhage, peptic ulcers, myopathy, rhabdomyolysis, gout, flushing, skin lesions, skin infections, lower respiratory infections, and increased incidence of diabetes and hospitalizations for diabetes [85] No restrictions for pregnant or breast feeding patients [87] |
Statins, isoniazid, and pyrazinamide [1,88] |
| Nigella Sativa | IIb | A | Reduces GI cholesterol absorption, increases biliary excretion, reduces cholesterol synthesis, inhibits lipid oxidation, upregulates LDL receptors [89] | 200 mg to 3 g for powders, capsules, and extracts 1 to 5 mL for oil suspensio ns [90] |
LDL-C: −0.48 mmol/L; 95% CI, –0.58 to −0.37 [90] | GI discomfort, elevated alkaline-phosphate, AST, ALT, gamma- glutamyl transferase [89] Safe to use during pregnancy [91] Insufficient data during breastfeeding [22] |
anticoagulants, anti- platelets, antidiabetic drugs, antihypertensives, cyclosporine, diuretics, immunosuppressants, and serotonergic drugs [22] |
| Olive Extract | IIb | B | Reduces lipid peroxidation, increases bile excretion, and inhibits HMG-CoA reductase and ACAT [92] | 136.2 mg oleuropei n and 6.4 mg hydroxyty rosol [93] | LDL-C: –0.19 ± SD 0.56 mmol/L [93] | No known adverse effects of olive extract No known data on about the levels consumed through olive extract in those who are pregnant or breastfeeding [94] | No known interactions [94] |
| Gamma-oryzanol | IIb | A | Inhibits GI absorption, increases excretion of bile acids, inhibits HMG- CoA reductase, inhibits platelet aggregation, [95] alters the gut microbiome [96] | 100 to 300 mg [16,22] | LDL-C: −5 to −10% [16] | No reported side effects [10,97] No safety data on patients who are pregnant or breastfeeding [22] |
No known drug interactions [22] |
| Pantethine | IIb | B | Inhibits HMG-CoA reductase and acetyl- CoA carboxylase, which are involved in TG synthesis and lipoprotein metabolism [98] | 600 to 1200 mg [98] | LDL-C: −11% [98] | gastrointestinal symptom [98] Safe in children and in patients with chronic kidney disease, including dialysis [99,100] Insufficient data in patients who are pregnant or breastfeeding [22] |
No known drug interactions [22] |
| Polyunsaturated n-3 Fatty Acids | I | A | Reduces synthesis of hepatic VLDL, endogenous fatty acids, substrates available for TG synthesis, and activity of diacylglycerol acyltransferase or phosphatidic acid phosphohydrolase, which are involved in TG synthesis, promotes β- oxidation of fatty acids and increase phospholipid synthesis [101] | ≤4 g [102,103] | TG: −0.36 mmol/L [104] | GI discomfort, new- onset atrial fibrillation and atrial flutter, fishy aftertaste [103,105] Safe to use in pregnancy [106] Likely safe during breastfeeding [22] |
Anticoagulants, anti- platelet drugs, antihypertensives, contraceptives, cyclosporine, and tacrolimus [22] |
| Pectin | IIb | B | Decreases GI cholesterol absorption, increases bile acid excretion, [107,108] decreases HMG-CoA reductase, increases cholesterol 7-α- hydroxylase in the liver, modulates gut microbiome [108] | 6 g [107] | LDL-C: −5 to −10% [16] | GI discomfort [107] Precaution in patients who are pregnant (binds to vitamin B12) [109] Safe in patients who are breastfeeding [22] |
Digoxin, lovastatin, and tetracyclines [22] |
| Phytosterols | IIa | A | Inhibit cholesterol absorption in GI tract by competing with dietary cholesterol in the formation of dietary micelles, decreasing apoB secretion from enterocytes and hepatocytes, increases expression of ABCA1 and ABCG1 level [110,111,112] | 400 mg to 3 g [16,110] | LDL-C: −8 to −16% [16,69] | Well tolerated and safe [16,69] Safe to use in pregnancy [113] Insufficient data on their use in those breastfeeding [22] |
No known drug interactions [22] |
| Policosanol | IIb | A | Promotes bile acid production and lipolysis via inhibiting the expression of farnesoid X receptor-small heterodimer partner and activating the Takeda G- coupled protein receptor 5-AMPK signaling pathway, which inhibits HMG-CoA reductase activity [114,115] | 5 to 20 mg [116] | LDL-C: −0.71 mmol/L; 95% CI, –1.02 to −0.40 [116] | GI discomfort, tachycardia, myalgia, hypertension, headache, dizziness, somnolence, insomnia, polydipsia, nocturia, dry skin, rashes, and weight gain [116] Safe to use in pregnancy [117,118] Insufficient data in breastfeeding [22] |
Antidiabetic drugs, beta-blockers, nitroprusside, and warfarin [22] |
| Probiotics | IIb | A |
Lactobacillus and Bifidobacterium increase bile acid excretion [119] Lacticaseibacillus decreases NPC1L1 cholesterol transporter expression and increase cholesterol efflux via increased expression of ABCA1 [120] Lactobacillus rhamnosus JL1 activates the AMPK pathway and inhibits PPAR-γ and SREBP-1C gene expression [121] |
1 to 6 g [16,122] | LDL-C: −5% [16] | GI discomfort, infections from yeast Saccharomyces cervisiae Safe in infants and patients who are pregnant or breastfeeding [123] | Insufficient data [16] |
| Red Yeast Rice Extract | I | A | HMG-CoA reductase inhibitor [124] | <3 mg of monacolin K) [14] | LDL-C: −15% to −25% [16] | Gastrointestinal discomfort, rashes, and allergic reactions [17,20,21] Formulations with citrinin are nephrotoxic and hepatotoxic [14,20,21] No elevations in transaminases or kidney impairment [14,17,20,21] Precautions with pregnancy [125] Unknown if safe to use during breastfeeding [126] |
CYPP450 inducers or inhibitors, antifungals, macrolides, cyclosporine, fibrates, niacin, nefazodone, protease inhibitors, statins, and verapamil [16,126] |
| Resveratrol | III | A | Activates silent information regulation 2 homolog 1, suppresses hepatic upregulation of genes associated in lipogenesis and prevent the downregulation of genes involved with lipolysis, [127] suppresses foam cell formation [128] | 250 to 3000 mg [129,130] | LDL-C: −0.147 mmol/L; 95% CI, –0.286 to −0.008 [131] | Increase bleeding Likely safe to consume during pregnancy and breastfeeding provided not consumed from alcohol. In patients with malignancies that grow in response to estrogen, such as breast cancer, uterine cancer, ovarian cancer, it is advised that patients should limit intake [129] |
Garlic, ginger, ginkgo, nattokinase, anticoagulants, anti- platelet drugs and those involving the cytochrome P450 system, such as CYP1A1, CYP1A2, CYP1B1, CYP2C19, CYP2E1, and CYP3A4 [129] |
| Sea Buckthorn | IIb | A | Increases expression of PPAR-α, PPAR-γ, and ABCA1, decreases expression of SREBP-2, promotes expression of CPT1A, which is involved in increasing lipolysis and β-oxidation [132] | 0.75 mL [133] | LDL-C: −0.40 mmol/L; 95% CI, –0.76 to −0.04 [133] | Well tolerated Safe to use in pregnancy [134] Little data in patients who breastfeed [22] |
Anticoagulants, anti- platelets, and antihypertensives [22] |
| Silymarin | IIb | A | Increases lipolysis and β- oxidation via the upregulation of CPT1, [135] increases cholesterol efflux via increases expression of ABCA1 [136] | 140 to 700 mg [137] | LDL-C: −0.27 mmol/L; 95% CI, –0.49 to −0.05 [137] | GI discomfort, headache, ureteric calculi, and hemolytic anemia, transient ischemia attack, myocardial infarction, and cardiovascular death [137] Insufficient data in patients who are pregnant or breastfeeding [138] | Antidiabetic drugs, morphine, tamoxifen, sirolimus, and warfarin [22] |
| Spirulina | IIa | A | Activates heme oxygenase-1 (atheroprotective enzyme involved in heme catabolic pathway in endothelial cells), [16,69] antioxidant, anti- inflammatory, and radical-scavenging properties, [16] alters gut microbiome [139] | 1 to 10 g [69] | LDL-C: −5 to −15% [16,69] | GI discomfort, bleeding, rashes, elevated transaminases, and cholestasis [22,140] Little safety data in patients who are pregnant or breastfeeding [22] | Anticoagulants, anti- platelets, antidiabetic drugs, and immunosuppressant drugs [22] |
| Soybean Protein | IIa | A | Inhibits HMG-CoA reductase, reduces PCSK9 protein, [141] increases bile acid excretion, cholesterol synthesis inhibition, increases transcription of the LDL receptor, [142,143] increases apoB receptor activity, decreases hepatic synthesis of cholesterol and lipoprotein secretion, [143] alters the gut microbiome [144] | 25 to 120 mg [16,69] | LDL-C: −3 to −10% [16] | GI discomfort, menstrual complaints, headaches, dizziness, and rashes [22] Chronic use of higher doses of soy protein may affect fertility and thyroid function [16,69] Decreased absorption of divalent and trivalent metals, such as calcium, copper, iron, magnesium, and zinc [143] Avoid during pregnancy Use of soy is likely safe during breastfeeding [22] |
Antidiabetic drugs, antihypertensive drugs, diuretics, estrogens, progesterone, tamoxifen, levothyroxine, monoamine oxidase inhibitors, and warfarin [22] |
| Vitamin E | IIb | A | Inhibits HMG-CoA reductase, promotes scavenging for free radicals, and activates PPAR -α, -β, and -γ receptors [145,146,147] | 400 to 800 UI [16] | HDL-C: 0.15 mmol/L; 95% CI, 0.07 to 0.23 [148] | Bleeding, heart failure, hemorrhagic cerebral vascular accidents, prostate cancer, and all- cause mortality [147,149] Safe in pregnancy [106] Likely safe during breastfeeding [22] |
Alkylating agents, anticoagulants, anti- platelets, cyclosporine, CYP3A4 substrates, niacin, and selumetinib [22] |
Definition of level of evidence. Level A: Data derived from multiple randomized clinical trials or their meta-analysis. Level B: Data derived from a single randomized clinical trial or large nonrandomized studies. Level C: Consensus or opinion of experts and/or small studies, retrospectives studies, or registries. Definition of classes of recommendation. Class I: Evidence and/or general agreement that a given treatment or procedure is beneficial, useful, and effective. Is recommended/ is indicated. Class II: Conflicting evidence and/or a divergence of opinion about the usefulness/efficacy of the given treatment or procedure. Class IIa: Weight of evidence/opinion is in favor of usefulness/ efficacy. Should be considered. Class IIb: Usefulness/efficacy is less well established by evidence/opinion. May be considered. Class III Evidence or general agreement that the given treatment or procedure is not useful/ effective and, in some cases, may be harmful. Is not recommended (no efficacy on lipid profile). Abbreviations: Acyl-coenzyme A cholesterol acyltransferase (ACAT), adenosine triphosphate-binding cassette (ABC), alanine-aminotransferase (ALA), adenosine monophosphate-activated protein kinase (AMPK), aspartate-aminotransferase (AST), carnitine palmitoyl transferase 1 (CPT1), gastrointestinal reabsorption (GI), high-density lipoprotein cholesterol (HDL-C), 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA), lecithin cholesterol acyltransferase (LCAT), low-density lipoprotein cholesterol (LDL-C), messenger ribonucleic acid (mRNA), nicotinamide adenine dinucleotide phosphate (NADPH), Niemann-Pick C1-like 1 (NPC1L1), peroxisome proliferator-activated receptor (PPAR), proprotein convertase subtilisin/kexin type 9 inhibitor (PCSK9I), red yeast rice (RYR), sterol regulatory element-binding proteins (SREBP), total cholesterol (TC), triglycerides (TG).