{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T19:50:27Z","timestamp":1790970627948,"version":"4.1.0"},"reference-count":36,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2020,10,14]],"date-time":"2020-10-14T00:00:00Z","timestamp":1602633600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Nutrients"],"abstract":"<jats:p>Phytosterols and red yeast rice are largely studied cholesterol-lowering nutraceuticals, respectively inhibiting the bowel absorption and liver synthesis of cholesterol. Our aim was to test the effect of combined nutraceutical-containing phytosterols and red yeast rice vs. a placebo on the lipid profile. We performed a parallel arms, double-blind, placebo-controlled clinical trial, randomizing 88 moderately hypercholesterolemic subjects to treatment with a combined nutraceutical containing phytosterols (800 mg) and red yeast rice, standardized to contain 5 mg of monacolins from Monascus purpureus, with added niacin (27 mg) and policosanols (10 mg) (LEVELIP DUO\u00ae), or placebo. The mean LDL-Cholesterol (LDL-C) change at Week 8 was \u221232.5 \u00b1 30.2 mg\/dL (\u221219.8%) in the combined nutraceutical group and 2.5 \u00b1 19.4 mg\/dL (2.3%) in the placebo group. The estimated between-group difference of \u221239.2 mg\/dL (95% CI: \u221248.6; \u221229.8) indicates a statistically significant difference between treatments in favor of the combined nutraceutical (p &lt; 0.0001). Total Cholesterol (TC), non-HDL cholesterol (non-HDL-C), Apolipoprotein B, TC\/HDL-C and LDL-C\/HDL-C improved in a similar way in the combined nutraceutical group only. No significant changes in other clinical and laboratory parameters were observed. In conclusion, the tested combined nutraceutical was well tolerated, while significantly reducing the plasma levels of LDL-C, TC, non-HDL-C, ApoB, TC\/HDL-C and LDL-C\/HDL-C ratios in mildly hypercholesterolemic patients. Trial registration (ClinicalTrials.gov): NCT03739242.<\/jats:p>","DOI":"10.3390\/nu12103127","type":"journal-article","created":{"date-parts":[[2020,10,13]],"date-time":"2020-10-13T22:02:02Z","timestamp":1602626522000},"page":"3127","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":24,"title":["A Randomized, Double-Blinded, Placebo-Controlled, Clinical Study of the Effects of a Nutraceutical Combination (LEVELIP DUO\u00ae) on LDL Cholesterol Levels and Lipid Pattern in Subjects with Sub-Optimal Blood Cholesterol Levels (NATCOL Study)"],"prefix":"10.3390","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4367-3884","authenticated-orcid":false,"given":"Arrigo F.G.","family":"Cicero","sequence":"first","affiliation":[{"name":"Medical an Surgery Sciences Department, Dyslipidemia and Atherosclerosis Research Unit, Alma Mater Studiorum University of Bologna, 40138 Bologna, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6631-4342","authenticated-orcid":false,"given":"Sergio","family":"D\u2019Addato","sequence":"additional","affiliation":[{"name":"Medical an Surgery Sciences Department, Dyslipidemia and Atherosclerosis Research Unit, Alma Mater Studiorum University of Bologna, 40138 Bologna, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8039-8781","authenticated-orcid":false,"given":"Claudio","family":"Borghi","sequence":"additional","affiliation":[{"name":"Medical an Surgery Sciences Department, Dyslipidemia and Atherosclerosis Research Unit, Alma Mater Studiorum University of Bologna, 40138 Bologna, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,10,14]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Bittner, V.A. (2019). The New 2019 ACC\/AHA Guideline on the Primary Prevention of Cardiovascular Disease. Circulation.","DOI":"10.1161\/CIRCULATIONAHA.119.040625"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1557","DOI":"10.1056\/NEJMra1806939","article-title":"Lipid Management for the Prevention of Atherosclerotic Cardiovascular Disease","volume":"381","author":"Michos","year":"2019","journal-title":"N. Engl. J. Med."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"508","DOI":"10.1097\/HCO.0000000000000763","article-title":"Nutrition and physical activity recommendations from the United States and European cardiovascular guidelines: A comparative review","volume":"35","author":"Ferraro","year":"2020","journal-title":"Curr. Opin. Cardiol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"2076","DOI":"10.1039\/C7FO00178A","article-title":"Food and plant bioactives for reducing cardiometabolic disease risk: An evidence based approach","volume":"8","author":"Cicero","year":"2017","journal-title":"Food Funct."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"731","DOI":"10.1093\/nutrit\/nux047","article-title":"Lipid-lowering nutraceuticals in clinical practice: Position paper from an International Lipid Expert Panel","volume":"75","author":"Cicero","year":"2017","journal-title":"Nutr. Rev."},{"key":"ref_6","unstructured":"Authors\/Task Force Members, ESC Committee for Practice Guidelines (CPG), and ESC National Cardiac Societies (2019). 2019 ESC\/EAS guidelines for the management of dyslipidaemias: Lipid modification to reduce cardiovascular risk. Atherosclerosis, 290, 140\u2013205."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"72","DOI":"10.1016\/S0002-9343(00)00366-1","article-title":"Effects of dietary phytosterols on cholesterol metabolism and atherosclerosis","volume":"109","author":"Goldstein","year":"2000","journal-title":"Am. J. Med."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"6704","DOI":"10.2174\/0929867326666190822154701","article-title":"Molecular Insights into the Mechanisms Underlying the Cholesterol-Lowering Effects of Phytosterols","volume":"26","year":"2019","journal-title":"Curr. Med. Chem."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"214","DOI":"10.1017\/S0007114514000750","article-title":"LDL-cholesterol-lowering effect of plant sterols and stanols across different dose ranges: A meta-analysis of randomised controlled studies","volume":"112","author":"Ras","year":"2014","journal-title":"Br. J. Nutr."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"31337","DOI":"10.1038\/srep31337","article-title":"Effects of plant stanol or sterol-enriched diets on lipid profiles in patients treated with statins: Systematic review and meta-analysis","volume":"6","author":"Han","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"134","DOI":"10.1093\/nutrit\/nuw059","article-title":"Interindividual variability in the cholesterol-lowering effect of supplementation with plant sterols or stanols","volume":"75","author":"Fumeron","year":"2017","journal-title":"Nutr. Rev."},{"key":"#cr-split#-ref_12.1","unstructured":"EFSA Panel on Dietetic Products, Nutrition and Allergies (NDA) (2014). Scientific Opinion on the modification of the authorisation of a health claim related to plant sterol esters and lowering blood LDL-cholesterol"},{"key":"#cr-split#-ref_12.2","unstructured":"high blood LDL-cholesterol is a risk factor in the development of (coronary) heart disease pursuant to Article 14 of Regulation (EC) No 1924\/2006, following a request in accordance with Article 19 of Regulation (EC) No 1924\/2006. EFSA J., 12, 3577."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"192","DOI":"10.14797\/mdcj-15-3-192","article-title":"Red Yeast Rice for Hypercholesterolemia","volume":"15","author":"Cicero","year":"2019","journal-title":"Methodist Debakey Cardiovasc. J."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"5220","DOI":"10.1021\/jf000338c","article-title":"Constituents of red yeast rice, a traditional Chinese food and medicine","volume":"48","author":"Ma","year":"2000","journal-title":"J. Agric. Food Chem."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"415","DOI":"10.1016\/j.atherosclerosis.2015.04.004","article-title":"Traditional Chinese lipid-lowering agent red yeast rice results in significant LDL reduction but safety is uncertain\u2014A systematic review and meta-analysis","volume":"240","author":"Gerards","year":"2015","journal-title":"Atherosclerosis"},{"key":"#cr-split#-ref_16.1","unstructured":"EFSA (2011). Scientific Opinion on the substantiation of health claims related to monacolin K from red yeast rice and maintenance of normal blood LDL-cholesterol concentrations (ID 1648, 1700) pursuant to Article 13 of Regulation (EC) No 1924\/20061"},{"key":"#cr-split#-ref_16.2","unstructured":"EFSA (2011). Scientific Opinion on the substantiation of health claims related to monacolin K from red yeast rice and maintenance of normal blood LDL-cholesterol concentrations (ID 1648, 1700) pursuant to Article 13 of Regulation"},{"key":"#cr-split#-ref_16.3","unstructured":"(EC) No 1924\/20061; EFSA Panel on Dietetic Products, Nutrition and Allergies (NDA), European Food Safety Authority (EFSA), Parma, Italy. EFSA J., 9, 2304."},{"key":"ref_17","unstructured":"EFSA (2018). Scientific opinion on the safety of monacolins in red yeast rice. EFSA Panel on Food Additives and Nutrient Sources added to Food (ANS). European Food Safety Authority (EFSA), Parma, Italy. EFSA J., 16, 5368."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.phrs.2019.02.028","article-title":"Safety of red yeast rice supplementation: A systematic review and meta-analysis of randomized controlled trials","volume":"143","author":"Fogacci","year":"2019","journal-title":"Pharmacol. Res."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"2094","DOI":"10.1002\/ptr.6402","article-title":"Three-arm, placebo-controlled, randomized clinical trial evaluating the metabolic effect of a combined nutraceutical containing a bergamot standardized flavonoid extract in dyslipidemic overweight subjects","volume":"33","author":"Cicero","year":"2019","journal-title":"Phytother. Res."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"631","DOI":"10.2459\/JCM.0000000000000855","article-title":"The role of physical activity in individuals with cardiovascular risk factors: An opinion paper from Italian Society of Cardiology-Emilia Romagna-Marche and SIC-Sport","volume":"20","author":"Nasi","year":"2019","journal-title":"J. Cardiovasc. Med."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1270","DOI":"10.1089\/jmf.2015.0024","article-title":"Testing the Short-Term Efficacy of a Lipid-Lowering Nutraceutical in the Setting of Clinical Practice: A Multicenter Study","volume":"18","author":"Cicero","year":"2015","journal-title":"J. Med. Food"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"273","DOI":"10.1016\/j.ctim.2005.07.008","article-title":"Antihyperlipidaemic effect of a Monascus purpureus brand dietary supplement on a large sample of subjects at low risk for cardiovascular disease: A pilot study","volume":"13","author":"Cicero","year":"2005","journal-title":"Complement. Ther. Med."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1007\/s00394-011-0297-x","article-title":"The effect of plant sterols on serum triglyceride concentrations is dependent on baseline concentrations: A pooled analysis of 12 randomised controlled trials","volume":"52","author":"Demonty","year":"2013","journal-title":"Eur. J. Nutr."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1966","DOI":"10.1007\/s12325-017-0580-1","article-title":"Short-Term Effects of a Combined Nutraceutical on Lipid Level, Fatty Liver Biomarkers, Hemodynamic Parameters, and Estimated Cardiovascular Disease Risk: A Double-Blind, Placebo-Controlled Randomized Clinical Trial","volume":"34","author":"Cicero","year":"2017","journal-title":"Adv. Ther."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"283","DOI":"10.1007\/s40292-017-0206-3","article-title":"Nutraceutical Effects on Glucose and Lipid Metabolism in Patients with Impaired Fasting Glucose: A Pilot, Double-Blind, Placebo-Controlled, Randomized Clinical Trial on a Combined Product","volume":"24","author":"Cicero","year":"2017","journal-title":"High. Blood Press Cardiovasc. Prev."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"562","DOI":"10.1097\/01.hjr.0000221866.27039.4b","article-title":"Favorable cardiovascular risk profile and 10-year coronary heart disease incidence in women and men: Results from the Progetto CUORE","volume":"13","author":"Palmieri","year":"2006","journal-title":"Eur. J. Cardiovasc. Prev. Rehabil."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1113","DOI":"10.1016\/j.phymed.2015.10.011","article-title":"Combinations of phytomedicines with different lipid lowering activity for dyslipidemia management: The available clinical data","volume":"23","author":"Cicero","year":"2016","journal-title":"Phytomedicine"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1007\/s00394-017-1582-0","article-title":"Mediterranean diet and cardiovascular disease: A systematic review and meta-analysis of observational studies","volume":"58","author":"Rosato","year":"2019","journal-title":"Eur. J. Nutr."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Cholesterol Treatment Trialists\u2019 (CTT) Collaboration (2010). Efficacy and safety of more intensive lowering of LDL cholesterol: A meta-analysis of data from 170000 participants in 26 randomised trials. Lancet, 376, 1670\u20131681.","DOI":"10.1016\/S0140-6736(10)61350-5"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1186\/s12986-017-0214-2","article-title":"Effect of a short-term dietary supplementation with phytosterols, red yeast rice or both on lipid pattern in moderately hypercholesterolemic subjects: A three-arm, double-blind, randomized clinical trial","volume":"14","author":"Cicero","year":"2017","journal-title":"Nutr. Metab."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"202","DOI":"10.1016\/j.atherosclerosis.2016.01.005","article-title":"Cosegregation of serum cholesterol with cholesterol intestinal absorption markers in families with primary hypercholesterolemia without mutations in LDLR, APOB, PCSK9 and APOE genes","volume":"246","author":"Jarauta","year":"2016","journal-title":"Atherosclerosis"},{"key":"#cr-split#-ref_32.1","unstructured":"EFSA Panel on Dietetic Products, Nutrition and Allergies (NDA) (2009). Scientific Opinion on the substantiation of health claims related to niacin and energy-yielding metabolism (ID 43, 49, 54), function of the nervous system (ID 44, 53), maintenance of the skin and mucous membranes (ID 45, 48, 50, 52), maintenance of normal LDL-cholesterol, HDL-cholesterol and triglyceride concentrations (ID 46), maintenance of bone (ID 50), maintenance of teeth (ID 50), maintenance of hair (ID 50, 2875) and maintenance of nails (ID 50, 2875) pursuant to Article 13 of Regulation"},{"key":"#cr-split#-ref_32.2","unstructured":"(EC) No 1924\/2006 on request from European Commission. EFSA J., 7, 1224."}],"container-title":["Nutrients"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6643\/12\/10\/3127\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T10:20:46Z","timestamp":1760178046000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6643\/12\/10\/3127"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,10,14]]},"references-count":36,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2020,10]]}},"alternative-id":["nu12103127"],"URL":"https:\/\/doi.org\/10.3390\/nu12103127","relation":{},"ISSN":["2072-6643"],"issn-type":[{"value":"2072-6643","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,10,14]]}}}