{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,3]],"date-time":"2026-10-03T16:51:23Z","timestamp":1791046283662,"version":"4.1.0"},"reference-count":42,"publisher":"MDPI AG","issue":"21","license":[{"start":{"date-parts":[[2022,10,26]],"date-time":"2022-10-26T00:00:00Z","timestamp":1666742400000},"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>Growing evidence exists that consumption of cocoa-rich food improves the parameters of cardiometabolic health. These effects are ascribed to cocoa flavanols, particularly to (\u2013)-epicatechin (EC), a natural ingredient of cocoa. Hence, to evaluate if EC may explain the effects of cocoa, this systematic review aimed to provide an overview on randomized controlled trials (RCTs) investigating the impact of an EC intake on cardiometabolic biomarkers. For this, the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) 2020 statement was considered and the risk of bias (RoB) was assessed by using the Cochrane RoB 2 tool. In total, 11 studies were included examining parameters on vascular function, glucose\/lipid metabolism, oxidative stress, inflammation, appetite sensations, and body weight before and after EC treatment. Except for a dose-dependent acute increase in flow-mediated dilatation (FMD) and in the peripheral arterial tonometry (PAT) index in healthy young adults, effects by EC treatment were not observed. For most trials, some concerns exist for overall RoB. Thus, EC intake may improve endothelial function in healthy young adults. For further parameters (mostly secondary outcomes), it remains unclear if EC has no effect or if this was not detectable. Unbiased RCTs on the impact of an EC intake are needed, which should also investigate the additive or synergistic effects of EC with other cocoa ingredients.<\/jats:p>","DOI":"10.3390\/nu14214500","type":"journal-article","created":{"date-parts":[[2022,10,26]],"date-time":"2022-10-26T07:17:48Z","timestamp":1666768668000},"page":"4500","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["Effect of an (\u2013)-Epicatechin Intake on Cardiometabolic Parameters\u2014A Systematic Review of Randomized Controlled Trials"],"prefix":"10.3390","volume":"14","author":[{"given":"Lisa","family":"Dicks","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zeina","family":"Haddad","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefanie","family":"Deisling","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9988-9406","authenticated-orcid":false,"given":"Sabine","family":"Ellinger","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,10,26]]},"reference":[{"key":"ref_1","unstructured":"World Health Organization (WHO) (2022, July 04). Cardiovascular Diseases (CVDs). Available online: https:\/\/www.who.int\/news-room\/fact-sheets\/detail\/cardiovascular-diseases-(cvds)."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"740","DOI":"10.3945\/ajcn.111.023457","article-title":"Effects of chocolate, cocoa, and flavan-3-ols on cardiovascular health: A systematic review and meta-analysis of randomized trials","volume":"95","author":"Hooper","year":"2012","journal-title":"Am. J. Clin. Nutr."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1982","DOI":"10.3945\/jn.111.145482","article-title":"Flavonoid-rich cocoa consumption affects multiple cardiovascular risk factors in a meta-analysis of short-term studies","volume":"141","author":"Shrime","year":"2011","journal-title":"J. Nutr."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"2325","DOI":"10.3945\/jn.116.237644","article-title":"Cocoa flavanol intake and biomarkers for cardiometabolic health: A systematic review and meta-analysis of randomized controlled trials","volume":"146","author":"Lin","year":"2016","journal-title":"J. Nutr."},{"key":"ref_5","first-page":"CD008893","article-title":"Effect of cocoa on blood pressure","volume":"8","author":"Ried","year":"2012","journal-title":"Cochrane Database Syst. Rev."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"879","DOI":"10.1038\/ejcn.2011.64","article-title":"Effects of cocoa products\/dark chocolate on serum lipids: A meta-analysis","volume":"65","author":"Tokede","year":"2011","journal-title":"Eur. J. Clin. Nutr."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"102240","DOI":"10.1016\/j.ctim.2019.102240","article-title":"The effect of cocoa consumption on markers of oxidative stress: A systematic review and meta-analysis of interventional studies","volume":"48","author":"Mehrabani","year":"2020","journal-title":"Complementary Ther. Med."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"2349","DOI":"10.1080\/10408398.2018.1451820","article-title":"Does cocoa\/dark chocolate supplementation have favorable effect on body weight, body mass index and waist circumference? A systematic review, meta-analysis and dose-response of randomized clinical trials","volume":"59","author":"Ghaedi","year":"2019","journal-title":"Crit. Rev. Food Sci. Nutr."},{"key":"ref_9","first-page":"e21649","article-title":"Timing of chocolate intake affects hunger, substrate oxidation, and microbiota: A randomized controlled trial","volume":"35","author":"Escobar","year":"2021","journal-title":"FASEB J."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"European Food Safety Authority (2014). Scientific opinion on the modification of the authorisation of a health claim related to cocoa flavanols and maintenance of normal endothelium dependent vasodilation pursuant to Article 13(5) of Regulation (EC) No 1924\/2006 following request in accordance with Article 19 of Regulation (EC) No 1924\/2006. EFSA J., 12, 3654.","DOI":"10.2903\/j.efsa.2014.3654"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1490","DOI":"10.1093\/ajcn\/nqac055","article-title":"Effect of cocoa flavanol supplementation for the prevention of cardiovascular disease events: The COcoa Supplement and Multivitamin Outcomes Study (COSMOS) randomized clinical trial","volume":"115","author":"Sesso","year":"2022","journal-title":"Am. J. Clin. Nutr."},{"key":"ref_12","unstructured":"U.S. Department of Agriculture (USDA) (2022, July 04). USDA Database for the Flavonoid Content of Selected Foods. Release 3.2 (November 2015), Available online: https:\/\/data.nal.usda.gov\/dataset\/usda-database-flavonoid-content-selected-foods-release-32-november-2015."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"237","DOI":"10.1016\/j.freeradbiomed.2010.11.005","article-title":"The stereochemical configuration of flavanols influences the level and metabolism of flavanols in humans and their biological activity in vivo","volume":"50","author":"Ottaviani","year":"2011","journal-title":"Free Radic. Biol. Med."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1365","DOI":"10.3945\/ajcn.111.029330","article-title":"Epicatechin ingested via cocoa products reduces blood pressure in humans: A nonlinear regression model with a Bayesian approach","volume":"95","author":"Ellinger","year":"2012","journal-title":"Am. J. Clin. Nutr."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1016\/j.mam.2018.01.007","article-title":"Plant bioactives and redox signaling: (\u2013)-Epicatechin as a paradigm","volume":"61","author":"Fraga","year":"2018","journal-title":"Mol. Asp. Med."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"478","DOI":"10.1016\/j.freeradbiomed.2018.11.010","article-title":"(\u2013)-Epicatechin in the control of glucose homeostasis: Involvement of redox-regulated mechanisms","volume":"130","author":"Cremonini","year":"2019","journal-title":"Free Radic. Biol. Med."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"108505","DOI":"10.1016\/j.abb.2020.108505","article-title":"(\u2212)-Epicatechin and the comorbidities of obesity","volume":"690","author":"Cremonini","year":"2020","journal-title":"Arch. Biochem. Biophys."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"186","DOI":"10.3164\/jcbn.12-130","article-title":"Flavan 3-ols improve metabolic syndrome risk factors: Evidence and mechanisms","volume":"52","author":"Osakabe","year":"2013","journal-title":"J. Clin. Biochem. Nutr."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"178","DOI":"10.1016\/j.jclinepi.2021.03.001","article-title":"The PRISMA 2020 statement: An updated guideline for reporting systematic reviews","volume":"134","author":"Page","year":"2021","journal-title":"J. Clin. Epidemiol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"948","DOI":"10.1093\/ajcn\/nqy066","article-title":"A nutritive dose of pure (\u2212)-epicatechin does not beneficially affect increased cardiometabolic risk factors in overweight-to-obese adults: A randomized, placebo-controlled, double-blind crossover study","volume":"107","author":"Kirch","year":"2018","journal-title":"Am. J. Clin. Nutr."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"l4898","DOI":"10.1136\/bmj.l4898","article-title":"RoB 2: A revised tool for assessing risk of bias in randomised trials","volume":"366","author":"Sterne","year":"2019","journal-title":"BMJ"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1024","DOI":"10.1073\/pnas.0510168103","article-title":"(\u2212)-Epicatechin mediates beneficial effects of flavanol-rich cocoa on vascular function in humans","volume":"203","author":"Schroeter","year":"2006","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1018","DOI":"10.1093\/ajcn\/88.4.1018","article-title":"Pure dietary flavonoids quercetin and (\u2212)-epicatechin augment nitric oxide products and reduce endothelin-1 acutely in healthy men","volume":"88","author":"Loke","year":"2008","journal-title":"Am. J. Clin. Nutr."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"2379","DOI":"10.1002\/mnfr.201600045","article-title":"Does epicatechin contribute to the acute vascular function effects of dark chocolate? A randomized, crossover study","volume":"60","author":"Dower","year":"2016","journal-title":"Mol. Nutr. Food Res."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"613","DOI":"10.3945\/ajcn.115.129783","article-title":"Epicatechin, procyanidins, cocoa, and appetite: A randomized controlled trial","volume":"104","author":"Greenberg","year":"2016","journal-title":"Am. J. Clin. Nutr."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"2197","DOI":"10.1039\/C6FO00248J","article-title":"Acute effects of chlorogenic acids on endothelial function and blood pressure in healthy men and women","volume":"7","author":"Ward","year":"2016","journal-title":"Food Funct."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"746","DOI":"10.1016\/j.clnu.2019.03.041","article-title":"Acute study of dose-dependent effects of (\u2212)-epicatechin on vascular function in healthy male volunteers: A randomized controlled trial","volume":"39","author":"Castle","year":"2020","journal-title":"Clin. Nutr."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"914","DOI":"10.3945\/ajcn.114.098590","article-title":"Effects of the pure flavonoids epicatechin and quercetin on vascular function and cardiometabolic health: A randomized, double-blind, placebo-controlled, crossover trial","volume":"101","author":"Dower","year":"2015","journal-title":"Am. J. Clin. Nutr."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1459","DOI":"10.3945\/jn.115.211888","article-title":"Supplementation of the pure flavonoids epicatechin and quercetin affects some biomarkers of endothelial dysfunction and inflammation in (pre)hypertensive adults: A randomized double-blind, placebo-controlled, crossover trial","volume":"145","author":"Dower","year":"2015","journal-title":"J. Nutr."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"500","DOI":"10.1016\/j.ijcard.2016.08.158","article-title":"A randomized, placebo-controlled, double-blind study on the effects of (\u2212)-epicatechin on the triglyceride\/HDLc ratio and cardiometabolic profile of subjects with hypertriglyceridemia: Unique in vitro effects","volume":"223","author":"Meaney","year":"2016","journal-title":"Int. J. Cardiol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1911","DOI":"10.1093\/jn\/nxy236","article-title":"Quercetin, but not epicatechin, decreases plasma concentrations of methylglyoxal in adults in a randomized, double-blind, placebo-controlled, crossover trial with pure flavonoids","volume":"148","author":"Geleijnse","year":"2018","journal-title":"J. Nutr."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"29034","DOI":"10.1038\/srep29034","article-title":"The metabolome of [2-14C](\u2212)-epicatechin in humans: Implications for the assessment of efficacy, safety, and mechanisms of action of polyphenolic bioactives","volume":"6","author":"Ottaviani","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"H3043","DOI":"10.1152\/ajpheart.00190.2006","article-title":"Age and flow-mediated dilation: A comparison of dilatory responsiveness in the brachial and popliteal arteries","volume":"291","author":"Parker","year":"2006","journal-title":"Am. J. Physiol.-Heart Circ. Physiol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1403","DOI":"10.1016\/j.freeradbiomed.2011.12.010","article-title":"Structurally related (\u2212)-epicatechin metabolites in humans: Assessment using de novo chemically synthesized authentic standards","volume":"52","author":"Ottaviani","year":"2012","journal-title":"Free Radic. Biol. Med."},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Esser, D., Geleijnse, J.M., Matualatupauw, J.C., Dower, J.I., Kromhout, D., Hollman, P.C.H., and Afman, L.A. (2018). Pure flavonoid epicatechin and whole genome gene expression profiles in circulating immune cells in adults with elevated blood pressure: A randomised double-blind, placebo-controlled, crossover trial. PLoS ONE, 13.","DOI":"10.1371\/journal.pone.0194229"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1641","DOI":"10.1002\/ptr.5665","article-title":"The impact of cocoa flavanols on cardiovascular health","volume":"30","author":"Vlachojannis","year":"2016","journal-title":"Phytother. Res."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"352","DOI":"10.3945\/ajcn.116.140046","article-title":"Methylxanthines enhance the effects of cocoa flavanols on cardiovascular function: Randomized, double-masked controlled studies","volume":"105","author":"Sansone","year":"2017","journal-title":"Am. J. Clin. Nutr."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"719","DOI":"10.1016\/j.clnu.2017.06.007","article-title":"Theobromine does not affect postprandial lipid metabolism and duodenal gene expression, but has unfavorable effects on postprandial glucose and insulin responses in humans","volume":"37","author":"Smolders","year":"2018","journal-title":"Clin. Nutr."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1201","DOI":"10.3945\/ajcn.112.047373","article-title":"Effect of cocoa and theobromine consumption on serum HDL-cholesterol concentrations: A randomized controlled trial","volume":"97","author":"Neufingerl","year":"2013","journal-title":"Am. J. Clin. Nutr."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1229","DOI":"10.1093\/ajcn\/nqy229","article-title":"Assessing the respective contributions of dietary flavanol monomers and procyanidins in mediating: Randomized, controlled, double-masked intervention trial cardiovascular effects in humans","volume":"108","author":"Weber","year":"2018","journal-title":"Am. J. Clin. Nutr."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1716","DOI":"10.1111\/1471-0528.15199","article-title":"Randomised controlled trials\u2014The gold standard for effectiveness research","volume":"125","author":"Hariton","year":"2018","journal-title":"BJOG"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"c332","DOI":"10.1136\/bmj.c332","article-title":"CONSORT 2010 Statement: Updated guidelines for reporting parallel group randomised trials","volume":"340","author":"Schulz","year":"2010","journal-title":"BMJ"}],"container-title":["Nutrients"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6643\/14\/21\/4500\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T01:03:13Z","timestamp":1760144593000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6643\/14\/21\/4500"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,10,26]]},"references-count":42,"journal-issue":{"issue":"21","published-online":{"date-parts":[[2022,11]]}},"alternative-id":["nu14214500"],"URL":"https:\/\/doi.org\/10.3390\/nu14214500","relation":{},"ISSN":["2072-6643"],"issn-type":[{"value":"2072-6643","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,10,26]]}}}