Cocoa Flavanol Intake and Biomarkers for Cardiometabolic Health: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.
BACKGROUND
Cocoa flavanols may improve cardiometabolic health. Evidence from small short-term randomized clinical trials (RCTs) remains inconsistent, and large long-term RCTs testing the efficacy of cocoa flavanols are still lacking.


OBJECTIVE
We performed a systematic review and meta-analysis of RCTs to quantify the effect of cocoa flavanol intake on cardiometabolic biomarkers.


METHODS
We searched PubMed, Web of Science, and the Cochrane Library for RCTs that evaluated the effects of cocoa flavanols on biomarkers relevant to vascular disease pathways among adults. Data were extracted following a standardized protocol. We used DerSimonian and Laird random-effect models to compute the weighted mean differences (WMDs) and 95% CIs. We also examined potential modification by intervention duration, design, age, sex, comorbidities, and the form and amount of cocoa flavanol intake.


RESULTS
We included 19 RCTs that comprised 1131 participants, and the number of studies for a specific biomarker varied. The amount of cocoa flavanols ranged from 166 to 2110 mg/d, and intervention duration ranged from 2 to 52 wk. Cocoa flavanol intake significantly improved insulin sensitivity and lipid profile. The WMDs between treatment and placebo were -0.10 mmol/L (95% CI: -0.16, -0.04 mmol/L) for total triglycerides, 0.06 mmol/L (95% CI: 0.02, 0.09 mmol/L) for HDL cholesterol, -2.33 μIU/mL (95% CI: -3.47, -1.19 μIU/mL) for fasting insulin, -0.93 (95% CI: -1.31, -0.55) for the homeostatic model assessment of insulin resistance, 0.03 (95% CI: 0.01, 0.05) for the quantitative insulin sensitivity check index, 2.54 (95% CI: 0.63, 4.44) for the insulin sensitivity index, -0.83 mg/dL (95% CI: -0.88, -0.77 mg/dL) for C-reactive protein, and 85.6 ng/mL (95% CI: 16.0, 155 ng/mL) for vascular cell adhesion molecule 1. No significant associations were found for other biomarkers. None of the modifiers seemed to qualitatively modify the effects of cocoa flavanol intake.


CONCLUSIONS
Our study suggests that cocoa flavanol intake has favorable effects on select cardiometabolic biomarkers among adults. These findings support the need for large long-term RCTs to assess whether cocoa flavanol intake reduces the risk of diabetes and cardiovascular events.
Department of Epidemiology and Center for Global Cardiometabolic Health, Brown University, Providence, RI.
Xiaochen
X
Lin
Department of Epidemiology and Center for Global Cardiometabolic Health, Brown University, Providence, RI.
Isabel
I
Zhang
Oxford College of Emory University, Oxford, GA.
Alina
A
Li
Division of Preventive Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA.|Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA; and.
JoAnn E
JE
Manson
Division of Preventive Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA.|Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA; and.
Howard D
HD
Sesso
Division of Preventive Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA.
Lu
L
Wang
Department of Epidemiology and Center for Global Cardiometabolic Health, Brown University, Providence, RI; simin_liu@brown.edu.|Division of Preventive Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA.|Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA; and.|Division of Endocrinology, Department of Medicine, Warren Alpert Medical School and Rhode Island Hospital, Providence, RI.
Simin
S
Liu
D015415:Biomarkers; D002099:Cacao / Q000737:chemistry*; D002318:Cardiovascular Diseases / Q000517:prevention & control*; D044948:Flavonols / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans
D015415:Biomarkers; D044948:Flavonols
biomarkers; cardiometabolic health; cocoa flavanols; meta-analysis; randomized controlled trials
Am J Clin Nutr. 2012 Mar;95(3):740-51
22301923
J Nutr. 2008 Sep;138(9):1671-6
18716168
Arch Biochem Biophys. 2010 Sep 1;501(1):112-5
20494650
Neurology. 2012 Sep 18;79(12):1223-9
22933736
Am J Clin Nutr. 2007 Mar;85(3):709-17
17344491
J Nutr. 2006 Dec;136(12):3039-45
17116717
J Nutr. 2014 Mar;144(3):335-43
24368432
Stat Med. 2002 Jun 15;21(11):1539-58
12111919
J Agric Food Chem. 2011 Nov 9;59(21):11862-71
21932846
Int J Cardiol. 2013 Oct 15;168(6):5448-50
23295039
Am J Clin Nutr. 2009 Nov;90(5):1144-50
19776136
J Agric Food Chem. 2005 Nov 2;53(22):8506-11
16248545
Biometrics. 1994 Dec;50(4):1088-101
7786990
Food Funct. 2012 Oct;3(10):1035-43
22796902
Neurology. 2013 Mar 19;80(12):1173-4
23509051
Diabetes Care. 2012 Feb;35(2):226-32
22250063
Adv Nutr. 2011 Jan;2(1):1-7
22211184
J Nutr. 2011 Nov;141(11):1982-8
21956956
Int J Obes (Lond). 2012 May;36(5):735-43
21750518
Control Clin Trials. 1986 Sep;7(3):177-88
3802833
JAMA. 2003 Aug 27;290(8):1030-1
12941674
Mol Nutr Food Res. 2013 Jun;57(6):948-61
23637048
Pharmacol Res. 2012 Sep;66(3):207-12
22728690
Circulation. 2014 Jan 21;129(3):e28-e292
24352519
Clin Sci (Lond). 2006 Jul;111(1):71-80
16551272
Am J Public Health. 2013 Jul;103(7):1207-18
23678895
Biometrics. 2000 Jun;56(2):455-63
10877304
Lancet. 1996 Sep 21;348(9030):834
8814019
Curr Opin Clin Nutr Metab Care. 2013 Nov;16(6):662-8
24100673
BMJ. 2011 Aug 26;343:d4488
21875885
Hypertension. 2012 Sep;60(3):794-801
22892813
Am J Hypertens. 2010 Jan;23(1):97-103
19910929
J Am Coll Nutr. 2007 Aug;26(4):373S-388S
17906191
Cochrane Database Syst Rev. 2012 Aug 15;(8):CD008893
22895979
Maturitas. 2011 Aug;69(4):312-21
21665390
Int J Mol Sci. 2010 Mar 31;11(4):1365-402
20480025
Curr Opin Lipidol. 2013 Feb;24(1):25-33
23254472
Hypertension. 2005 Aug;46(2):398-405
16027246
Int J Cardiol. 2011 May 19;149(1):83-8
20036019
Arch Biochem Biophys. 2012 Nov 15;527(2):95-104
22465028
Br J Nutr. 2014 Jan 14;111(1):122-34
23823716
J Clin Epidemiol. 2000 Nov;53(11):1119-29
11106885
J Nutr. 2000 Aug;130(8S Suppl):2120S-6S
10917933
Am J Clin Nutr. 2008 Dec;88(6):1685-96
19064532
J Am Coll Cardiol. 2008 Jun 3;51(22):2141-9
18510961
Ann Intern Med. 2009 Aug 18;151(4):264-9, W64
19622511
Int J Obes (Lond). 2008 Aug;32(8):1289-96
18504447
Am J Clin Nutr. 2013 Aug;98(2):340-8
23803878
Am J Clin Nutr. 2008 Jul;88(1):38-50
18614722
Br J Nutr. 2014 Feb;111(4):653-61
24274771
Nutr Metab (Lond). 2006 Jan 03;3:2
16390538
Nutrition. 2007 Apr;23(4):351-5
17350804
Int J Endocrinol. 2014;2014:653561
25254044
Am J Clin Nutr. 2005 Mar;81(3):611-4
15755830
BMJ. 1997 Sep 13;315(7109):629-34
9310563
Am J Clin Nutr. 2012 Apr;95(4):925-33
22357723
Eur J Nutr. 2014 Feb;53(1):149-58
23494741
Am J Clin Nutr. 2000 Jul;72(1):30-5
10871557
Diabet Med. 2010 Nov;27(11):1318-21
20968113
Int J Cardiol. 2009 Jan 24;131(3):424-9
18045712
BMJ. 2011 Oct 18;343:d5928
22008217
Am J Clin Nutr. 2013 Jun;97(6):1201-9
23595874
Diabetes Care. 2013 Dec;36(12 ):3961-70
24130345
Lancet. 1996 Nov 30;348(9040):1514
8942794