The Expert Panel defined the scope of the guideline to focus on flavan-3-ol intake and risk of cardiometabolic disease in the general adult population. This recommendation is written from the perspective of individual decision-making rather than a public health perspective. As such, the target audience for this guideline was the general adult population including healthy individuals as well as those with overweight or obesity and those who are at risk of chronic disease.The systematic review/meta-analysis informing this guideline development was based on the published manuscript by Raman et al. . This review systematically examined available evidence from both randomized controlled trials and prospective cohort studies in adults to evaluate the potential effects of flavan-3-ol intake on cardiometabolic health. Included studies should have quantified the amount of flavan-3-ol consumed per day or per week, and comparators included studies with low flavan-3-ol content,no flavan-3-ol intake, or placebo. From 1946 to March 2019, a systematic search of multiple databases was conducted , and studies were screened for inclusion or exclusion [Figure 1 in Raman et al. ]. A total of 157 randomized controlled trials and 15 cohort studies met the eligibility criteria.
All included studies were critically appraised for risk of bias,u planting gutter with relevant data extracted from included studies. Descriptive synthesis of evidence was conducted for all identified outcomes, and when possible, meta-analysis was conducted. For continuous data, results were summarized as mean difference between treatment groups with 95% CI, and dichotomous outcomes were reported as ORs or RRs with 95% CIs. The published systematic review/meta-analysis by Raman et al. was reviewed in depth by the Expert Panel and vetted critically on the strength of systematic review methods employed, synthesis of evidence, and strength of evidence rating/quality or grading using the AMSTAR 2 tool .The Expert Panel and the guideline development team used GRADE’s EtD framework to help translate available evidence into a recommendation statement. The purpose of the EtD framework is to use evidence in a structured and transparent manner to help develop recommendation statements. Along with the EtD framework, the framework for developing recommended intakes of bioactive dietary substances by Yates et al. was also used to guide the development of this recommendation statement. The Expert Panel individually and blindly completed GRADE’s EtD framework, used evidence summaries on effects of flavan-3- ol intakes on health outcomes, reviewed benefits and harms, certainty of evidence, outcome importance, resource use and equity, patient values, and acceptability and feasibility of a recommendation to increase flavan-3-ol intake.
The results of the EtD survey and implications of those judgments for the recommendation were reviewed by the Expert Panel members. Each Expert Panel member completed the EtD framework to provide a justification for having a recommendation for this topic. There was a consensus to write a recommendation based on the results of the EtD framework. Multiple web calls were conducted to identify core concepts/ideas that needed to be included, with the wording of the recommendation discussed at length. After much discussion and multiple rounds of editing to reach consensus, a recommendation statement was developed and accepted unanimously by the Expert Panel. The guidelines underwent an external peer review evaluation by recruited subject matter experts using the AGREE II tool . Comments from external reviewers were collated by the guideline development team and sent to the Expert Panel for discussion and editorial consideration. The Expert Panel Chair coordinated the final revision of the guideline document based on review comments.Among the general adult population, we suggest increasing consumption of nutrient-dense foods rich in flavan-3-ols and low in added sugars, including but not limited to tea, apples, berries, and cocoa. Based on moderate quality research, consumption of 400–600 mg/d flavan-3- ols can reduce risk associated with cardiovascular disease and diabetes. Increasing consumption of dietary flavan-3-ols may help improve blood pressure, cholesterol concentrations, and blood sugar. A continually growing body of research demonstrates higher consumption may reduce the risk of certain cardiometabolic disease and related mortality.
This is a food-based guideline and not a recommendation for flavan- 3-ol supplements because these may cause gastrointestinal irritation and/or liver injury, particularly when taken in excess or on an empty stomach.The Academy of Nutrition and Dietetics, National Academies of Science, Engineering, and Mathematics, and most experts agree that clinical practice guidelines should be based on high-quality systematic reviews of evidence . Our recommendation reflects careful consideration of the systematic review/meta-analysis by Raman et al. along with other scientific evidence reporting on flavan-3-ols and cardiometabolic health outcomes with much supporting data reported herein . Not only was the strength of evidence considered, but the Expert Panel also considered the magnitude of benefits and harms, costs, barriers and facilitators, resource and feasibility issues, and implementation factors. Strength of recommendation was assigned based on the Expert Panel’s evaluation of the totality of evidence, benefits and harms, consistency, clinical effect, and both generalizability and applicability. The influence of flavan-3-ols on cardiometabolic risk factors served as the basis for the recommendation statement, although again, strength of evidence was stronger for some biomarkers . Dose consistency among various meta-analyses including data from randomized clinical trials and observational studies supports the 400–600 mg/d recommendation for cardiometabolic health. The Expert Panel also considered the European Food Safety Authority Panel on Dietetic Products, Nutrition, and Allergies’ Scientific Opinions authorizing the health claim on consumption of cocoa flavanols and maintenance of normal endothelium-dependent vasodilation, and the specific proposed concentrations for proanthocyanidins and catechins by the Chinese Nutrition Society . Although the small effects exerted by flavan-3-ols on individual biomarkers might seem clinically insignificant in isolation, it has been noted that each 2-mmHg increase in systolic blood pressure increases mortality due to ischemic heart disease and stroke by 7% and 10%, respectively . As another example, a 0.026-mmol/L increase in HDL cholesterol concentrations has been reported to reduce CVD risk by 2–3% . Similarly, a 1% reduction in CVD risk has been reported with either a 1% reduction in LDL cholesterol or 1% increment in HDL cholesterol concentrations . Taken collectively, the cumulative improvements, albeit modest, in multiple biomarkers shown across the current scientific literature could have substantial benefits to overall risk reduction at both the individual and public health level. To better understand the protective effects of flavan-3- ols, it is important to first consider their bioaccessibility and bioavailability. Due to extensive metabolism by both human and microbial systems, metabolites are the main forms present in circulation and available for tissue uptake, metabolism, and biological activity . During absorption in the small intestine, flavan- 3-ols can be subjected to metabolic activities in enterocytes . Next, hepatic phase II conjugation with methyl, sulfate, and glucuronide conjugation alters their polarity, after which metabolites can be recycled back into the small intestine by biliary excretion . The human microbiota is capable of efficiently metabolizing flavan-3-ols and their conjugated metabolites into smaller molecular weight compounds that are efficiently absorbed into the bloodstream and detected in human urine. A variety of flavan-3-ol metabolites have been detected in human plasma postingestion, which can be freely circulating or bound to proteins in the bloodstream. It has been suggested that after entering the bloodstream,planting gutter flavan-3-ols interact with a series of complex molecular mechanisms that mediate CVD . Furthermore, direct interactions between flavan-3-ols and the gut microbiome are likely to alter host immune and inflammatory status as well as microbiome diversity. For example, the activity of absorbed parent compounds and of microbial metabolites appears to involve action on key cell receptors or crosstalk between cell signaling pathways, ultimately differentially affecting various cells and tissues, depending on the cell phenotype and metabolic environment . The most documented cardiovascular activity of flavan- 3-ols is their positive effects on vasculature. For example, biomarker-estimated flavan-3-ol intake was inversely associated with reduced systolic and diastolic blood pressure in the EPIC Norfolk study . Additionally, flavan-3-ols have also been shown to reduce arterial stiffness .
The exact mechanisms behind these improvements likely include the enhanced bioavailability of endothelial-derived nitric oxide, decreasing superoxide-mediated nitric oxide breakdown, and improvement in serum lipids. To put this in perspective, just a 1% increase in FMD has been shown to reduce CVD risk by 8% and 13% in asymptomatic and diseased populations, respectively . Lastly, animal and in vitro studies provide emerging evidence that flavan-3- ols improve inflammatory status via the interference of prooxidant enzyme-signaling cascades and adhesion molecule expression ; however, fluctuations in background cytokine production contribute to difficulty in detecting subtle changes in inflammatory status. More recent evidence supporting the cardiovascular benefits derived from flavan-3-olswas published from the COSMOS randomized clinical trial evaluating a cocoa extract supplement in ∼21,000 older adults . Following a median treatment and follow-up period of 3.6 y, a significant 27% reduction in CVD deaths was observed as well as a significant 16% reduction in major cardiovascular events . Although it is critical to extend mortality follow-up, current results support long-term cardiovascular benefits through the provision of a flavan-3- ol–rich intervention. Additionally, a recent meta-analysis of cohort studies investigating the relation between flavonoid consumption and cardiovascular outcomes builds upon findings from Raman et al. . Individuals with the highest intake of flavan-3-ols, catechins, and proanthocyanidins had a 15%, 25%, and 17% significantly lower RR, respectively, of CVD compared with individuals with the lowest intake . Although Raman et al. found moderate evidence in prospective cohort studies that flavan-3-ol intake was associated with a reduced risk of CVD mortality, CHD, stroke, and type 2 diabetes mellitus, no association was shown for incidence of hypertension . However, a notable limitation in evaluation of these prospective cohort studies is the tool for assessing risk-of-bias. This tool did not include an “ascertainment of exposure” question, which is one of the unique challenges that should be considered in nutrition-related systematic reviews . Additionally, the majority of included prospective cohort studies within Raman et al. included only a single dietary assessment and, therefore, the data did not likely constitute moderate level evidence . Several other challenges/limitations arise regarding intake of flavan-3-ols using data from prospective cohort studies. First, if a substantial portion of the diet is replaced by a food high in flavan-3-ols, then total energy intake and other nutrients associated with plant food intake likely also improve. This can lead to the conclusion that a wide variety of flavan- 3-ol sources and amounts can provide a detectable health benefit. It remains unclear, however, how much of that benefit is directly attributable to the effects of flavan-3-ols compared with elimination of less healthy components from the diet, a reduced caloric intake, or increased consumption of other healthy dietary constituents. Additionally, it should be noted that confounding factors including potential effect modifiers and multicollinearity along with lack of adjustment for covariates might affect any observed association. These phenomena can also occur to a lesser extent in clinical trials of flavan-3-ol–rich foods. Despite challenges that arise from use of data from prospective cohort studies, the consistency among these investigations considered for this guideline support the Expert Panel recommendation of 400–600 mg/d flavan-3-ol intake for cardiometabolic health. Future prospective cohort studies would benefit from using omics technologies to identify and validate novel biomarkers of exposure to assist researchers in overcoming measurement error from assessing flavan-3-ol intake via FFQs. Additionally, although genetic instrumental variable analysis, commonly known as Mendelian randomization, cannot establish causality, it does have the potential to eliminate reverse-causation that is prevalent in traditional nutrition epidemiology. Of interest, a genetically predicted extra daily cup of tea consumption was associated with a decrease in small vessel stroke in a recent Mendelian randomization analysis of UK Biobank participants .The potential risks of increasing flavan-3-ol intake through supplementation are of concern and warrant elaboration. Concentrated green tea extracts and purified catechins, including the well-known epigallocatechin gallate , have been implicated in both benefits and harms from green tea. Liver injury and gastrointestinal distress are the most widely reported adverse effects associated with flavan- 3-ol consumption, mainly arising from supplementation with concentrated green tea extracts in a fasted state. Because intake recommendations should draw heavily upon toxicology tenets, the Expert Panel considered evidence from 3 high-quality systematic reviews and risk assessments when developing the guideline . The systematic reviews highlight numerous reports of potential green tea extract–mediated hepatotoxicity that suggest liver damage can occur after ingestion of bolus doses in high quantities for extended periods of time.