|Date: 01-15-2016||HC# 121531-536|
Ottaviani JI, Balz M, Kimball J, et al. Safety and efficacy of cocoa flavanol intake in healthy adults: a randomized, controlled, double-masked trial. Am J Clin Nutr. December 2015;102(6):1425-1435.
The intake of flavanols and procyanidins has been shown to benefit cardiovascular health in dietary intervention studies. In many trials, the intake amount of such plant-based bioactives exceeds the average, usual dietary intake by most people. However, the potential risks of a high-flavanol/procyanidin diet have not been specifically investigated in a prospective study. Therefore, the aim of this randomized, controlled, double-masked trial was to investigate the effects of cocoa (Theobroma cacao, Malvaceae) flavanol (CF) intake amount and duration on blood pressure (BP), platelet function, metabolic variables, and potential adverse events (AEs) in healthy adults with a low risk for cardiovascular disease. The authors hypothesized that a daily intake of up to 2000 mg CFs would be well-tolerated in healthy humans and would exert beneficial changes in BP and platelet function.
The authors recruited healthy men and women aged 30 to 55 years by public advertisement in Davis, California, and surrounding areas. Eligible subjects were screened through the use of health and lifestyle questionnaires. Height, weight, and in-office BP measurements were taken; blood samples were used to conduct a complete blood count (CBC) and liver, lipid, and metabolic panels.
The CF-containing test material for the study was made by using cocoa seed extract (CE) manufactured by the CocoaPro® extract process (Mars, Inc.; McLean, Virginia), which preserves flavanols and procyanidins. Each capsule contained 500 mg CFs. The cellulose-based control capsules contained the highly alkalized cocoa powder Jet Black (Blommer Chocolate Co.; Chicago, Illinois), with no detectable CF levels. Both study capsules were similar in macro- and micronutrients, theobromine and caffeine content, size, and overall appearance.
Conducted at Ragle Human Nutrition Center at the University of California, Davis, the trial included 2 parts. Thirty-seven subjects were recruited for part 1, beginning in April 2012. Part 1 was an open-label, intake-amount escalation study, in which healthy adults consumed escalating amounts of CFs, increasing from 1000 to 2000 mg daily over 6 weeks. Specifically, they consumed 1000 mg daily for 2 weeks, 1500 mg daily for 2 weeks, and 2000 mg daily for 2 weeks, followed by a 2-week washout period. They consumed their CE capsules at 2 separate times (with breakfast and lunch or with lunch and dinner). On study visit days 1, 15, 29, 43, and 57, the subjects underwent an in-office BP measurement and a blood draw. The subjects consumed 1 of their 2 daily doses at the study site (CF intakes of 500 mg at visit 1; 1000 mg at visits 2, 3, and 4; and no capsule at visit 5), with 250 mL water instead of a meal to assess absorption and metabolism.
AEs that occurred during the study were rated in severity from grade 1 (mild) to grade 2 (moderate) to grade 3 (severe) to grades 4 and 5 (serious). Each AE was determined to be not related, possibly related, probably related, or related to the study intervention.
During part 1, 48 mild AEs were reported by 27 subjects. Although no association was observed between CF intake amount and number of AEs reported, 94% occurred during the 6 weeks in which subjects consumed CE capsules and only 6% occurred during the 2-week washout period (P<0.001). Most (75%) AEs were gastrointestinal related, with nausea (44%) being the most often reported gastrointestinal-related AE. No significant changes in systolic or diastolic BP or platelet function were observed during study part 1.
Of the 37 subjects enrolled in part 1, 4 discontinued the intervention due to loss of inclusion criteria (1), time conflicts (2), and other reasons (1).
With recruitment beginning in June 2012, part 2 was a randomized, controlled, double-masked, 2-parallel-arm, dietary intervention study in which 74 healthy subjects were asked to consume up to 2000 mg CFs (n=46) or the CF-free control (n=28) daily for 12 weeks. During a run-in period, the subjects consumed 2 capsules daily (1000 mg CFs in the CF group) during week 1 and 3 capsules daily during week 2. After the run-in period, the subjects consumed 4 capsules daily (2000 mg CFs in the CF group) during weeks 3 to 12. During a 2-week follow-up washout period, no capsules were consumed.
Before each study visit, the subjects fasted for 12 hours and refrained from taking aspirin and ibuprofen for the preceding week. On days 1, 43, 85, and 99, the subjects underwent an in-office BP measurement and a blood draw. Their 24-hour ambulatory BP (ABP) was measured on study days 1 and 85.
During part 2, 46 AEs were reported by 31 subjects, with 28 reported by 19 subjects in the CF group and 18 by 12 subjects in the control group. The between-group differences were not significant. All AEs were mild, except for 1 moderate AE in the CF group. Gastrointestinal-related AEs represented 62% of all AEs reported, with no significant between-group differences. Most (93%) of the gastrointestinal-related AEs occurred within the first 6 weeks of the study.
Of the 74 enrolled subjects in part 2, 9 in the CF group discontinued intervention due to an AE (1), loss of inclusion criteria (2), time conflicts (5), and other reasons (1). In the control group, 5 discontinued intervention due to loss of inclusion criteria (1) and time conflicts (4).
The lower number of gastrointestinal-related AEs in part 2 compared with part 1 may be attributed to the fact that the subjects consumed the capsules on an empty stomach in part 1, not with food as in part 2, say the authors.
No clinically relevant changes in liver panels, metabolic panels, CBC results, or in-office BP or ABP were observed over time in the groups or between groups. According to the authors, the lack of any significant changes in BP or platelet function in either part of the study may be due to the fact that the subjects were healthy with a low risk for cardiovascular disease.
The authors also observed that the acute intake of CE capsules resulted in the presence of up to 1832 ± 968 nM structurally related (–)-epicatechin metabolites in plasma, and the daily intake of CE capsules resulted in the presence of up to 568 ± 784 nM 5-(3',4'-dihydroxyphenyl)-γ-valerolactone metabolites in plasma. The authors state that these results show "that CFs are indeed available for absorption when consumed in the CE capsule format tested in this study."
The authors conclude that intake of CFs in the form of CF-containing CE, providing up to 2000 mg CFs daily for 12 weeks, was well tolerated in healthy adults with a low risk for cardiovascular disease. They point out that the amount of CFs consumed and the duration of CF intake significantly exceeded those in earlier dietary intervention studies. The data from this study, along with results of earlier studies, "support the notion that the positive health effects previously reported to be associated with the intake of CFs can be achieved at intake amounts that are well below those that might result in an increased risk of CF-related AEs."
This study was partially supported by an unrestricted gift from Mars, Inc., and the company also provided the test materials and analytical standards as gifts. Four of the authors (J. Ottaviani, M. Balz, C. Kwik-Uribe, and H. Schroeter) are employed by Mars, Inc. Another author, Carl Keen, received an unrestricted research grant from Mars, Inc., and is the current holder of the Mars Chair in Developmental Nutrition.—Shari Henson